Spirocyclic compounds

ABSTRACT

The present invention provides compounds and intermediates. The present invention also provides compounds which bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and their use for the treatment of abnormal cellular proliferation. The present invention also provides compounds that may be used as synthetic intermediates in the synthesis of bifunctional compounds used for targeted protein degradation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/103,621, filed Nov. 24, 2020, which is a continuation ofInternational Application No. PCT/US2019/035233, filed in theInternational Patent Cooperation Treaty, U.S. Receiving Office on Jun.3, 2019, which claims the benefit of European Patent Application No.18175701.4, filed Jun. 4, 2018. The entirety of each of theseapplications is hereby incorporated by reference herein for allpurposes.

FIELD OF THE INVENTION

The present invention provides compounds which bind to the ubiquitouslyexpressed E3 ligase protein cereblon (CRBN), which can alter thesubstrate specificity of the CRBN E3 ubiquitin ligase complex, resultingin breakdown of intrinsic downstream proteins. The present inventionalso provides compounds that can be used as synthetic intermediates inthe preparation of bifunctional compounds for use in targeted proteindegradation. The present compounds are thus useful for the treatment orprophylaxis of abnormal cellular proliferation, including tumors andcancer.

BACKGROUND OF THE INVENTION

Protein degradation is a highly regulated and essential process thatmaintains cellular homeostasis. The selective identification and removalof damaged, misfolded, or excess proteins is achieved via theubiquitin-proteasome pathway (UPP). The UPP is central to the regulationof almost all cellular processes, including antigen processing,apoptosis, biogenesis of organelles, cell cycling, DNA transcription andrepair, differentiation and development, immune response andinflammation, neural and muscular degeneration, morphogenesis of neuralnetworks, modulation of cell surface receptors, ion channels and thesecretory pathway, the response to stress and extracellular modulators,ribosome biogenesis and viral infection.

Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitinligase to a terminal lysine residue marks the protein for proteasomedegradation, where the protein is digested into small peptides andeventually into its constituent amino acids that serve as buildingblocks for new proteins. Defective proteasomal degradation has beenlinked to a variety of clinical disorders including Alzheimer's disease,Parkinson's disease, Huntington's disease, muscular dystrophies,cardiovascular disease, and cancer among others.

There are over 600 E3 ubiquitin ligases which facilitate theubiquitination of different proteins in vivo, which can be divided intofour families: HECT-domain E3s, U-box E3s, monomeric RING E3s andmulti-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487)titled “Genome-wide and functional annotation of human E3 ubiquitinligases identifies MULAN, a mitochondrial E3 that regulates theorganelle's dynamics and signaling.”; Berndsen et al. (Nat. Struct. Mol.Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligasemechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434)titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem.2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures,new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014,14, 233-347) titled “Roles of F-box proteins in cancer.”

Cereblon is a protein that in humans is encoded by the CRBN gene. CRBNorthologs are highly conserved from plants to humans, which underscoresits physiological importance.

Cereblon forms part of an E3 ubiquitin ligase protein complex whichinteracts with damaged DNA binding protein 1 (DDB1), forming an E3ubiquitin ligase complex with Cullin 4 (CUL4A) and the E2-bindingprotein ROC1 (also known as RBX1) where it functions as a substratereceptor to select proteins for ubiquitination. Through a mechanism thathas not been completely elucidated, cereblon ubiquitination of targetproteins results in increased levels of fibroblast growth factor 8(FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates anumber of developmental processes, such as limb and auditory vesicleformation. The net result is that this E3 ubiquitin ligase complex isimportant for limb outgrowth in embryos. In the absence of cereblon,DDB1 forms a complex with DDB2 that functions as a DNA damage-bindingprotein.

In unrelated parallel research, Ito et al. (Science 2010, 327,1345-1350) titled “Identification of a Primary Target of ThalidomideTeratogenicity”, described that cereblon is a thalidomide bindingprotein. The study revealed that thalidomide-cereblon binding in vivomay be responsible for thalidomide teratogenicity. After the discoverythat thalidomide causes teratogenicity in the mid-1960's, the compoundand related structures were notwithstanding found to be useful asanti-inflammatory, anti-angiogenic and anti-cancer agents (see Bartlettet al. (Nat. Rev. Cancer 2004, 4, 314-322) titled “The Evolution ofThalidomide and Its Imid Derivatives as Anticancer Agents”). Thalidomidehas been approved for the treatment of certain neoplastic diseases,including multiple myeloma, and is currently under investigation for usein treating a variety of other types of cancer along with the structuralderivatives lenalidomide and pomalidomide (see Martiniani, R. et al.“Biological activity of lenalidomide and its underlying therapeuticeffects in multiple myeloma” Adv Hematol, 2012, 2012:842945; and Terpos,E. et al. “Pomalidomide: a novel drug to treat relapsed and refractorymultiple myeloma” Oncotargets and Therapy, 2013, 6:531).

The disclosure that thalidomide binds to the cereblon E3 ubiquitinligase led to research to investigate incorporating thalidomide andcertain derivatives into compounds for the targeted destruction ofproteins. Celgene has disclosed imids for similar uses, including thosein U.S. Pat. Nos. 6,045,501; 6,315,720; 6,395,754; 6,561,976; 6,561,977;6,755,784; 6,869,399; 6,908,432; 7,141,018; 7,230,012; 7,820,697;7,874,984; 7,959,566; 8,204,763; 8,315,886; 8,589,188; 8,626,531;8,673,939; 8,735,428; 8,741,929; 8,828,427; 9,056,120; 9,101,621; and9,101,622.

Patent applications filed by C4 Therapeutics, Inc., that describecompounds capable of binding to an E3 ubiquitin ligase and a targetprotein for degradation include: WO 2017/197051 titled “Amine-LinkedC3-Glutarimide Degronimers for Target Protein Degradation”; WO2017/197055 titled “Heterocyclic Degronimers for Target ProteinDegradation”; WO 2017/197036 titled “Spirocyclic Degronimers for TargetProtein Degradation”; WO 2017/197046 20 titled “C3-Carbon LinkedGlutarimide Degronimers for Target Protein Degradation”; WO 2017/197056titled “Bromodomain Targeting Degronimers for Target ProteinDegradation.”; and WO 2018/237026 titled “N/O-Linked Degrons andDegronimers for Protein Degradation.”

Other patent applications that describe protein degrading compoundsinclude: WO 2015/160845; WO 2016/105518; WO 2016/118666; WO 2016/149668;WO 2016/197032; WO 2016/197114; WO 2017/007612; WO 2017/011371; WO2017/011590; WO 2017/030814; WO 25 2017/046036; WO 2017/176708; WO2017/176957; WO 2017/176598; WO 2017/180417; WO 2018/052945; WO2018/052949; WO 2018/053354; WO 2018/071606; WO 2018/102067; WO2018/102725; WO 2018/118598; WO 2018/119357; WO 2018/119441; WO2018/119448; WO 2018/140809; WO 2018/144649; and WO 2018/226542. Otherrelevant patent applications include: WO 2013/020557; WO 2013/063560; WO2013/106643; WO 2016/011906; WO 2017/024318; and WO 2017/117473.

There is a need for new compounds and methods of treatment that bind tothe E3 ligase protein cereblon for use in the treatment of variousmedical conditions, notably abnormal cellular proliferation. There isalso a need for new compounds that may be used in the preparation ofbifunctional molecules that are used in the degradation of proteins thatare involved in disease processes.

SUMMARY OF THE INVENTION

In a first aspect, compounds and their uses and manufacture are providedthat bind to cereblon and enhance the ubiquitination of proteins by acereblon-containing E3 ubiquitin ligase complex, which results inprotein degradation and thus is useful for the treatment of abnormalcellular proliferation and other disorders as described herein. In asecond aspect, compounds are provided that contain a chemical moietycapable of binding to cereblon, which can be used as syntheticintermediates in the preparation of bifunctional compounds that causedegradation of a selected protein via the ubiquitin proteasome pathway(UPP).

The compounds described herein can be administered to a host, forexample, a human, in need thereof, in an effective amount, optionally asa pharmaceutically acceptable salt, and optionally in a pharmaceuticallyacceptable composition. The compounds can be administered for anytherapeutic indication which can be treated by modulating the functionor activity of the cereblon-containing E3 Ubiquitin Ligase ProteinComplex, including but not limited to the treatment of abnormal cellproliferation, such as cancer or a tumor. In certain embodiments, thecompounds as described herein can modulate the natural activity ofcereblon.

The invention includes new compounds of Formula I, Formula II, FormulaIII, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a,Formula VIII-b, Formula VIII-c, Formula IX, Formula X, Formula XI,Formula XII-a, Formula XII-b, Formula XII-c, Formula XIII, and FormulaXIV. In addition, the invention includes the use of compounds generallyin Formula XV for the treatment of a therapeutic condition that can betreated by modulating the function or activity of thecereblon-containing E3 Ubiquitin Ligase Protein Complex. The inventionalso includes the use of compounds generally in Formula XVI in thepreparation of bifunctional compounds that degrade a target protein bythe ubiquitin proteasome pathway (UPP). The invention also includescompounds of Formula XVII-a, Formula XVII-b, Formula XVII-c, FormulaXVII-d, Formula XVII-e, Formula XVII-f, and Formula XVII-g.

In one aspect, a compound is provided of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is selected from the group consisting of aryl and aryl substitutedwith R¹; and

R¹ is selected from the group consisting of: —C(═O)—O—C₁₋₆-alkyl; —COOH;—NH—(C═O)—C₁₋₆-alkyl; —NH₂; and —NO₂.

In another aspect, a compound is provided of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

A² is aryl substituted with R¹;

and all other variables are as defined herein.

In another aspect, a compound is provided of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

Y is NH or CH₂;

A³ is selected from the group consisting of heteroaryl and heteroarylsubstituted with R²; and

R² is selected from the group consisting of: —COOH; —C(═O)—O—C₁₋₆-alkyl;—NH₂; and —NO₂.

In another aspect, a compound is provided of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

A⁴ is aryl substituted with Ria; and

R^(1a) is selected from the group consisting of: —C(═O)—O—C₁₋₆-alkyl;—COOH; and —NO₂.

In another aspect, a compound is provided of Formula V:

or a pharmaceutically acceptable salt thereof, wherein all variables areas defined herein.

In another aspect, a compound is provided of Formula VI:

or a pharmaceutically acceptable salt thereof, wherein:

A⁵ is heteroaryl substituted with R^(2a); and

R^(2a) is selected from the group consisting of —COOH and—C(═O)—O—C₁₋₆-alkyl.

In another aspect, a compound is provided of Formula VII:

or a pharmaceutically acceptable salt thereof, wherein:

A⁶ is heteroaryl substituted with R²; and

all other variables are as defined herein.

In another aspect, a compound is provided of Formula VIII-a, VIII-b, orVIII-c:

or a pharmaceutically acceptable salt thereof; wherein:

m is 0 or 1; and

all other variables are as defined herein.

In another aspect, a compound is provided of Formula IX:

or a pharmaceutically acceptable salt thereof, wherein:

n is 0 or 1; and

all other variables are as defined herein.

In another aspect, a compound is provided of Formula X:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In another aspect, a compound is provided of Formula XI:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In another aspect, a compound is provided of Formula XII-a, XII-b, orXII-c:

or a pharmaceutically acceptable salt thereof, wherein:

R^(2b) is selected from the group consisting of: —COOH;—C(═O)—O—C₁₋₆-alkyl; and —NO₂; and

all other variables are as defined herein.

In another aspect, a compound is provided of Formula XIII:

or a pharmaceutically acceptable salt thereof; wherein all variables areas defined herein.

In another aspect, a compound is provided of Formula XIV:

or a pharmaceutically acceptable salt thereof, wherein all variables areas defined herein.

The present invention provides compounds of Formula XV, or apharmaceutically acceptable salt thereof,

wherein the substituents and variables are as described below and in theclaims, or a pharmaceutically acceptable salt thereof.

The present compounds are useful for the therapeutic and/or prophylactictreatment of cancer.

The compounds of the present invention can further be used as part ofbifunctional compounds that comprise the compounds of present inventionas E3 Ubiquitin Ligase moiety that is linked to a moiety that binds to atarget protein where the target protein is proximate to the ubiquitinligase to effect degradation of said protein.

In another aspect, the use of a compound for the treatment of atherapeutic condition which can be treated by modulation the function oractivity of the cereblon containing E3 Ubiquitin Ligase Protein Complexis provided of Formula XV:

or a pharmaceutically acceptable salt thereof, wherein:

A is selected from the group consisting of: aryl; aryl substituted byR¹; heteroaryl; and heteroaryl substituted by R²; and

all over variables are as defined herein.

For clarity, as used herein, and A both refer the same group which isselected from aryl; aryl substituted by R¹; heteroaryl; and heteroarylsubstituted by R².

The compounds of Formula I, Formula II, Formula III, Formula IV, FormulaV, Formula VI, Formula VII, Formula VIII-a to Formula VIII-c, FormulaIX, Formula X, Formula XI, Formula XII-a to XII-c, Formula XIII, FormulaXIV, and Formula XV are useful as therapeutic agents when administeredin an effective amount to a host, typically a human, for the treatmentof a medical disorder including, but not limited to, abnormal cellularproliferation, including a tumor or cancer, or a myelo- orlymphoproliferative disorder such as B- or T-cell lymphomas, multiplemyeloma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or apost-transplant lymphoproliferative disorder; an immune disorder,including autoimmune disorder such as Addison disease, Celiac disease,Dermatomyositis, Graves disease, thyroiditis, multiple sclerosis,pernicious anemia, reactive arthritis, lupus, or type I diabetes; adisease of cardiologic malfunction including hypercholesterolemia; aninfectious disease including viral or bacterial infections; inflammatoryconditions including asthma, chronic peptic ulcers, tuberculosis,rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn'sdisease, or hepatitis.

In certain embodiments, the present invention provides theadministration of an effective amount of a compound of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII,Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI,Formula XII-a to XII-c, Formula XIII, Formula XIV, and Formula XV totreat a patient, for example a human, having an infectious disease,wherein the therapy acts via binding to cereblon or its E3 UbiquitinLigase or acts through an independent mechanism, optionally incombination with another bioactive agent. The disease state or conditionmay be caused by a microbial agent or other exogenous agent such as avirus (as non-limiting examples, HIV, HBV, HCV, HSV, HPV, RSV, CMV,Ebola, Flavivirus, Pestivirus, Rotavirus, Influenza, Coronavirus, EBV,viral pneumonia, drug-resistant viruses, Bird Flu, RNA virus, DNA virus,adenovirus, poxvirus, Picornavirus, Togavirus, Orthomyxovirus,Retrovirus, or Hepadovirus), bacterial (including but not limited toGram-negative, Gram-positive, Atypical, Staphylococcus, Streptococcus,E. Coli, Salmonella, Helicobacter pylori, meningitis, gonorrhea,Chlamydiaceae, Mycoplasmataceae, etc.), fungus, protozoa, helminth,worm, prion, parasite, or other microbe.

In another aspect, the compounds disclosed can be used as syntheticintermediates in the preparation of bifunctional compounds that causedegradation of a selected protein via the ubiquitin proteosome pathway(UPP) is provided. These compounds contain a functional group that canreact with a second compound, wherein the second compound is capable ofbinding to a selected protein of interest, to create a bifunctionalcompound as described above that can cause the degradation of theselected protein via the UPP.

Thus, a compound of Formula XVI, or a pharmaceutically acceptable saltthereof, is provided:

wherein:

Ax is selected from aryl or heteroaryl;

“Tail” is a chemical moiety that contains a reactive functional groupthat can covalently bind to a protein binding moiety to produce atargeted protein degrader, or

“Tail is a chemical moiety that can be used to modify the properties ofthe compound such as hydrophobility, hydrophilicity, solubility, drugdelivery, pharmacokinetics, or other properties such as charge,polarity, or fit within the active pocket;

-   -   in one embodiment, “Tail” is T,

wherein T is

X²¹ is selected from bond, NR³⁴, CH₂, CHR³⁴, C(R³⁴)₂, O, and S;

X²² is a functional group that can be used as a linking group to aprotein binding moiety; or X²² is a group that caps the valence and isnot typically a linking group; representative examples of X²² include,but are not limited to, halo, —NH₂, —NHR³⁴, —N(R³⁴)₂, hydroxyl, thiol,—B(OH)₂, —Sn(R³⁶)₃, —Si(R³⁶)₃, —OS(O)₂alkyl, —OS(O)₂haloalkyl, alkenyl,alkynyl, ethynyl, ethenyl, —C(O)H, —NR³⁴C(O)alkene, —NR³⁴C(O)alkyne,cyano, —SC(O)alkyl, OC(O)alkyl, heterocycle, —C(O)OH, hydrogen, alkyl,aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocyclic;

R³⁴ and R^(34′) are independently selected at each occurrence fromhydrogen, C₁-C₆alkyl (for example methyl, ethyl, cyclopropyl, orC₁-C₃alkyl), C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, C₃-C₆heterocycle, aryl, heteroaryl, —(CO)R³⁶, —(CS)R³⁶,—(C═NH)R³⁶, —(SO)R³⁶, and —(SO₂)R³⁶;

R³⁶ is independently selected at each occurrence from hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,C₃-C₆heterocycle, aryl, heteroaryl, hydroxyl, C₁-C₆alkoxy, thio,C₁-C₆thioalkyl, —NH₂, —NH(C₁-C₆alkyl, C₃-C₇cycloalkyl, C₃-C₇heterocycle,aryl, or heteroaryl), and —N(independently C₁-C₆alkyl, C₃-C₇cycloalkyl,C₃-C₇heterocycle, aryl, or heteroaryl)₂;

R²⁰, R²¹, R²², R²³, and R²⁴ are independently a divalent or multivalentlinking group, including but not limited to a covalent bond, alkyl,—C(O)—, —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO₂—,—S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—,—S—, —NH—, —N(alkyl)-, —CH(—O—R²⁶)—, —CH(—NR³⁴R^(34′))—,—C(—O—R²⁶)alkyl-, —C(—NR³⁴R^(34′))alkyl-, —C(R⁴⁰R⁴⁰)—,-alkyl(R²⁷)-alkyl(R²⁸)—, —C(R²⁷R²⁸)—, —P(O)(OR²⁶)O—, —P(O)(OR²⁶)—,—NR³⁴C(O)NR^(34′)—, alkene, haloalkyl, alkoxy, alkyneheteroarylalkyl,aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl,lactic acid, glycolic acid, carbocycle, -(ethylene glycol)₁₋₆-,-(lactic-co-glycolic acid)₁₋₆-, -(propylene glycol)₁₋₆-,—O—(CH₂)₁₋₁₂—O—, —NH—(CH₂)₁₋₁₂—NH—, —NH—(CH₂)₁₋₁₂—O—, —O—(CH₂)₁₋₁₂—NH—,—S—(CH₂)₁₋₁₂—O—, —O—(CH₂)₁₋₁₂—S—, —S—(CH₂)₁₋₁₂—S—, —S—(CH₂)₁₋₁₂—NH—, and—NH—(CH₂)₁₋₁₂—S—, wherein the 1-6 can be independently 1, 2, 3, 4, 5, or6, wherein the 1-12 can be independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12, and wherein one or more of the CH₂ or NH groups can bemodified by substitution of a H for a methyl, ethyl, cyclopropyl, F (ifon carbon), etc, as described herein, and optionally, a heteroatom,heteroalkyl, aryl, heteroaryl or cycloaliphatic group is interspersed inthe chain. Certain non-limiting examples include—O—CH(CH₃)—CH(CH₃)CH—O—, —O—CH₂—CH(CH₃)CH—O—, —O—CH(CH₃)—CH₂CH—O—, etc.

each of which R²⁰, R²¹, R²², R²³, and R²⁴ is optionally substituted withone or more substituents selected from R¹⁰¹ or alternatively asdescribed in the Definitions section; wherein at least one of R²⁰, R²¹,R²², R²³, and R²⁴ is not a bond;

R¹⁰¹ is independently selected at each occurrence from hydrogen, alkyl,alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl,heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy,heteroaryloxy, CN, —COOalkyl, COOH, NO₂, F, Cl, Br, I, CF₃, NH₂,NHalkyl, N(alkyl)₂, aliphatic, and heteroaliphatic;

R²⁶ is selected from hydrogen, alkyl, silane, arylalkyl,heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic,aliphatic and heteroaliphatic;

R²⁷ and R²⁸ are independently selected from hydrogen, alkyl, amine, ortogether with the carbon atom to which they are attached, form C(O),C(S), C═CH₂, a C₃-C₆ spirocarbocycle, or a 4-, 5-, or 6-memberedspiroheterocycle comprising 1 or 2 heteroatoms selected from N and O, orform a 1 or 2 carbon bridged ring;

R⁴⁰ is selected at each instance from: hydrogen, alkyl, alkene, alkyne,halogen, hydroxyl, alkoxy, azide, amino, cyano, —NH(aliphatic, includingalkyl), —N(aliphatic, including alkyl)₂, —NHSO₂(aliphatic, includingalkyl), —N(aliphatic, including alkyl)SO₂alkyl, —NHSO₂(aryl, heteroarylor heterocyclic), —N(alkyl)SO₂(aryl, heteroaryl or heterocyclic)—NHSO₂alkenyl, —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl,haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl,heterocyclic, and carbocyclic; and

all other variables are as defined herein.

In one embodiment the compound of Formula XVI can be used in thepreparation of compounds that cause degradation of a selected proteinvia the UPP are provided:

In one aspect, a compound is provided of one of the following formulas:

or a pharmaceutically acceptable salt thereof, wherein all variables areas defined herein.

In a first aspect, the present invention provides compounds of FormulaI, Formula II, Formula III, Formula IV, Formula V, Formula VI, FormulaVII, Formula VIII-a to Formula VIII-c, Formula IX, Formula X, FormulaXI, Formula XII-a to XII-c, Formula XIII, Formula XIV, Formula XV,Formula XVI, and Formula XVII-a to XVII-g as defined herein for use as atherapeutically active substance.

In a further aspect, the present invention provides pharmaceuticalcompositions comprising a compound of Formula I, Formula II, FormulaIII, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a toFormula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a toXII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI, and FormulaXVII-a to XVII-g as defined herein and a therapeutically inert carrier.

In certain embodiments, the compound of Formula I, Formula II, FormulaIII, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a toFormula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a toXII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI, and FormulaXVII-a to XVII-g has at least one desired isotopic substitution of anatom, at an amount above the natural abundance of the isotope, i. e.,enriched. In one embodiment, the compound of Formula I, Formula II,Formula III, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, FormulaXII-a to XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI, andFormula XVII-a to XVII-g includes a deuterium or multiple deuteriumatoms.

The present compounds are useful for the therapeutic and/or prophylactictreatment of cancer.

The compounds of the present invention can further be used as part ofbifunctional compounds that comprise the compounds of present inventionas E3 Ubiquitin Ligase moiety that is linked to a moiety that binds to atarget protein where the target protein is proximate to the ubiquitinligase to effect degradation of said protein.

Other features and advantages of the present application will beapparent from the following detailed description and claims.

The present invention therefore includes at least the followingfeatures:

-   -   a) a compound of Formula I, Formula II, Formula III, Formula IV,        Formula V, Formula VI, Formula VII, Formula VIII-a to Formula        VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to        XII-c, Formula XIII, Formula XIV, XVI, and Formula XVII-a to        XVII-g or a pharmaceutically acceptable salt thereof,    -   b) use of a compound of Formula I, Formula II, Formula III,        Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a        to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula        XII-a to XII-c, Formula XIII, Formula XIV, Formula XV, Formula        XVI, and Formula XVII-a to XVII-g or a pharmaceutically        acceptable salt thereof, in an effective amount in the treatment        of a patient, typically a human, with a disorder that responds        to such treatment, including by modulating the cereblon-based        ubiquitination of a protein, such as for example, abnormal        cellular proliferation such as a tumor or cancer, an immune or        autoimmune or inflammatory disorder, a cardiologic disorder, an        infectious disease, or other disorder that responds to such        treatment;    -   c) use of a compound of Formula I, Formula II, Formula III,        Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a        to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula        XII-a to XII-c, Formula XIII, Formula XIV, Formula XV, Formula        XVI, and Formula XVII-a to XVII-g or a pharmaceutically        acceptable salt thereof, in the manufacture of a medicament for        the treatment of a medical disorder, as further described        herein;    -   d) a method for manufacturing a medicament intended for the        therapeutic treatment of a disorder in a host, characterized in        that a compound of Formula I, Formula II, Formula III, Formula        IV, Formula V, Formula VI, Formula VII, Formula VIII-a to        Formula VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a        to XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI,        and Formula XVII-a to XVII-g is used in the manufacture;    -   e) a compound of Formula I, Formula II, Formula III, Formula IV,        Formula V, Formula VI, Formula VII, Formula VIII-a to Formula        VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to        XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI, and        Formula XVII-a to XVII-g or a pharmaceutically acceptable salt        thereof, that are useful in the treatment of an abnormal        cellular proliferation such as cancer in a host, including any        of the cancers described herein;    -   f) use of a compound of Formula I, Formula II, Formula III,        Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a        to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula        XII-a to XII-c, Formula XIII, Formula XIV, Formula XV, Formula        XVI, and Formula XVII-a to XVII-g or a pharmaceutically        acceptable salt thereof, in the manufacture of a medicament for        the treatment of an abnormal cellular proliferation such as        cancer, including any of the cancers described herein;    -   g) a method for manufacturing a medicament intended for the        therapeutic use of treating an abnormal cellular proliferation        such as cancer in a host, including any of the cancers described        herein, characterized in that a compound of Formula I, Formula        II, Formula III, Formula IV, Formula V, Formula VI, Formula VII,        Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula        XI, Formula XII-a to XII-c, Formula XIII, Formula XIV, Formula        XV, Formula XVI, and Formula XVII-a to XVII-g is used in the        manufacture;    -   h) a compound of Formula I, Formula II, Formula III, Formula IV,        Formula V, Formula VI, Formula VII, Formula VIII-a to Formula        VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to        XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI, and        Formula XVII-a to XVII-g or a pharmaceutically acceptable salt        thereof, that is useful in the treatment of a tumor in a host,        including any of the tumors described herein;    -   i) use of a compound of Formula I, Formula II, Formula III,        Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a        to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula        XII-a to XII-c, Formula XIII, Formula XIV, Formula XV, Formula        XVI, and Formula XVII-a to XVII-g or a pharmaceutically        acceptable salt thereof, in the manufacture of a medicament for        the treatment of a tumor in a host, including any of the tumors        described herein;    -   j) a method for manufacturing a medicament intended for the        therapeutic use of treating a tumor in a host, including any of        the tumors described herein, characterized in that a compound of        Formula I, Formula II, Formula III, Formula IV, Formula V,        Formula VI, Formula VII, Formula VIII-a to Formula VIII-c,        Formula IX, Formula X, Formula XI, Formula XII-a to XII-c,        Formula XIII, Formula XIV, Formula XV, Formula XVI, and Formula        XVII-a to XVII-g is used in the manufacture;    -   k) a compound of Formula I, Formula II, Formula III, Formula IV,        Formula V, Formula VI, Formula VII, Formula VIII-a to Formula        VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to        XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI, and        Formula XVII-a to XVII-g or a pharmaceutically acceptable salt        thereof, that is useful in the treatment of an immune,        autoimmune, or inflammatory disorder in a host;    -   l) use of a compound of Formula I, Formula II, Formula III,        Formula IV, Formula V, Formula VI, Formula VII, Formula VIII-a        to Formula VIII-c, Formula IX, Formula X, Formula XI, Formula        XII-a to XII-c, Formula XIII, Formula XIV, Formula XV, Formula        XVI, and Formula XVII-a to XVII-g or a pharmaceutically        acceptable salt thereof, in the manufacture of a medicament for        the treatment of an immune, autoimmune, or inflammatory disorder        in a host;    -   m) a method for manufacturing a medicament intended for the        therapeutic use of treating an immune, autoimmune, or        inflammatory disorder in a host, characterized in that a        compound of Formula I, Formula II, Formula III, Formula IV,        Formula V, Formula VI, Formula VII, Formula VIII-a to Formula        VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to        XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI, and        Formula XVII-a to XVII-g is used in the manufacture;    -   n) a pharmaceutical formulation comprising an effective        host-treating amount of a compound of a compound of Formula I,        Formula II, Formula III, Formula IV, Formula V, Formula VI,        Formula VII, Formula VIII-a to Formula VIII-c, Formula IX,        Formula X, Formula XI, Formula XII-a to XII-c, Formula XIII,        Formula XIV, Formula XV, Formula XVI, and Formula XVII-a to        XVII-g or a pharmaceutically acceptable salt thereof, with a        pharmaceutically acceptable carrier or diluent;    -   o) a compound of Formula I, Formula II, Formula III, Formula IV,        Formula V, Formula VI, Formula VII, Formula VIII-a to Formula        VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a to        XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI, and        Formula XVII-a to XVII-g as described herein in enantiomerically        or diastereomerically (as relevant) enriched form, including an        isolated enantiomer or diastereomer (i.e., greater than 85, 90,        95, 97, or 99% pure);    -   p) a process for the preparation of therapeutic products that        contain an effective amount of a compound of Formula I, Formula        II, Formula III, Formula IV, Formula V, Formula VI, Formula VII,        Formula VIII-a to Formula VIII-c, Formula IX, Formula X, Formula        XI, Formula XII-a to XII-c, Formula XIII, Formula XIV, Formula        XV, Formula XVI, and Formula XVII-a to XVII-g or a        pharmaceutically acceptable salt thereof; and    -   q) a process for the preparation of a bifunctional compound that        causes degradation of a selected protein via the ubiquitin        proteasome pathway, characterized in that a compound of XVI or        XVII-a to XVII-g is used in the preparation of the bifunctional        compound.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

The term “C₁₋₆-alkyl”, alone or in combination with other groups, standsfor a hydrocarbon radical which may be linear or branched, with singleor multiple branching, wherein the alkyl group in general comprises 1 to6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl(i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl(tert-butyl), isopentyl, 2-ethyl-propyl (2-methyl-propyl),1,2-dimethyl-propyl and the like. A specific group is methyl.

The term “heteroaryl” denotes a monovalent heterocyclic mono- orbicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4heteroatoms selected from N, O and S, the remaining ring atoms beingcarbon and in which all rings are aromatic. Examples of heteroarylmoieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl,thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl,diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl,indolinyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl,benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl,benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl,quinolinyl, isoquinolinyl, dihydroquinolyl, dihydropyrrolopyridinyl,dihydronaphthyridinyl, chromanyl, tetrahydroquinolinyl,dihydrocyclopentapyridinyl quinazolinyl, or quinoxalinyl. Particularexamples are pyridinyl, benzo[d]thiazolyl, pyrazolo[1,5-a]pyridinyl andthiazolo[4,5-b]pyridin-2-yl.

In one embodiment “heteroaryl” is a 5 membered aromatic group containing1, 2, 3, or 4 nitrogen atoms.

Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole,furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole,oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole,and thiatriazole.

Additional non-limiting examples of 5 membered “heteroaryl” groupsinclude:

In one embodiment “heteroaryl” is a 6 membered aromatic group containing1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl,pyrimidinyl, and pyrazinyl).

Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2nitrogen atoms include:

In one embodiment “heteroaryl” is a 9 membered bicyclic aromatic groupcontaining 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic includeindole, benzofuran, isoindole, indazole, benzimidazole, azaindole,azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole,benzoisothiazole, benzooxazole, and benzothiazole.

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

In one embodiment “heteroaryl” is a 10 membered bicyclic aromatic groupcontaining 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic includequinoline, isoquinoline, quinoxaline, phthalazine, quinazoline,cinnoline, and naphthyridine.

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

In an alternative embodiment “heteroaryl” is “optionally substituted”with 1, 2, 3, or 4 substituents.

The term “aryl” denotes a monovalent aromatic carbocyclic mono- orbicyclic ring system comprising 6 to 10 carbon ring atoms and in whichat least one ring is aromatic. Examples of aryl moieties include phenyl(Ph), indanyl, 1,2,3,4-tetrahydronaphthalenyl and naphthyl. Particularexamples are phenyl and 1,2,3,4-tetrahydronaphthalenyl.

In one embodiment “aryl” is a 6 carbon aromatic group (phenyl)

In one embodiment “aryl” is a 10 carbon aromatic group (napthyl)

In an alternative embodiment “aryl” is “optionally substituted” with 1,2, 3, or 4 substituents.

“Alkenyl” is a linear or branched aliphatic hydrocarbon groups havingone or more carbon-carbon double bonds that may occur at a stable pointalong the chain. The specified ranges as used herein indicate an alkenylgroup having each member of the range described as an independentspecies, as described above for the alkyl moiety. In one non-limitingembodiment, the alkenyl contains from 2 to about 12 carbon atoms, moregenerally from 2 to about 6 carbon atoms or from 2 to about 4 carbonatoms. In certain embodiments the alkenyl is C₂, C₂-C₃, C₂-C₄, C₂-C₅, orC₂-C₆. Examples of alkenyl radicals include, but are not limited toethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Theterm “alkenyl” also embodies “cis” and “trans” alkenyl geometry, oralternatively, “E” and “Z” alkenyl geometry. The term “Alkenyl” alsoencompasses cycloalkyl or carbocyclic groups possessing at least onepoint of unsaturation.

“Alkynyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon triple bonds that may occur at anystable point along the chain. The specified ranges as used hereinindicate an alkynyl group having each member of the range described asan independent species, as described above for the alkyl moiety. In onenon-limiting embodiment, the alkynyl contains from 2 to about 12 carbonatoms, more generally from 2 to about 6 carbon atoms or from 2 to about4 carbon atoms. In certain embodiments the alkynyl is C₂, C₂-C₃, C₂-C₄,C₂-C₅, or C₂-C₆. Examples of alkynyl include, but are not limited to,ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,4-hexynyl and 5-hexynyl.

“Halo” and “Halogen” is independently fluorine, chlorine, bromine oriodine.

“Haloalkyl” is a branched or straight-chain alkyl groups substitutedwith 1 or more halo atoms described above, up to the maximum allowablenumber of halogen atoms. Examples of haloalkyl groups include, but arenot limited to, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.“Perhaloalkyl” means an alkyl group having all hydrogen atoms replacedwith halogen atoms. Examples include but are not limited to,trifluoromethyl and pentafluoroethyl.

In one embodiment “haloalkyl” is a C₁-C₁₀haloalkyl, C₁-C₉haloalkyl,C₁-C₈haloalkyl, C₁-C₇haloalkyl, C₁-C₆haloalkyl, C₁-C₈haloalkyl,C₁-C₄haloalkyl, C₁-C₃haloalkyl, and C₁-C₂haloalkyl.

In one embodiment “haloalkyl” has one carbon.

In one embodiment “haloalkyl” has one carbon and one halogen.

In one embodiment “haloalkyl” has one carbon and two halogens.

In one embodiment “haloalkyl” has one carbon and three halogens.

In one embodiment “haloalkyl” has two carbons.

In one embodiment “haloalkyl” has three carbons.

In one embodiment “haloalkyl” has four carbons.

In one embodiment “haloalkyl” has five carbons.

In one embodiment “haloalkyl” has six carbons.

Non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

The term “heterocycle” denotes saturated and partially saturatedheteroatom-containing ring radicals, wherein there are 1, 2, 3, or 4heteroatoms independently selected from nitrogen, sulfur, boron,silicone, and oxygen. Heterocyclic rings may comprise monocyclic 3-10membered rings, as well as 5-16 membered bicyclic ring systems (whichcan include bridged, fused, and spiro-fused bicyclic ring systems). Itdoes not include rings containing —O—O—, —O—S— or —S—S-portions.Examples of saturated heterocycle groups include saturated 3- to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocycle radicalsinclude but are not limited to, dihydrothienyl, dihydropyranyl,dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated andsaturated heterocycle groups include but are not limited to,pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl,dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl,1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl.

Heterocycle” also includes groups wherein the heterocyclic radical isfused/condensed with an aryl or carbocycle radical, wherein the point ofattachment is the heterocycle ring. “Heterocycle” also includes groupswherein the heterocyclic radical is substituted with an oxo group (i.e.

). For example a partially unsaturated condensed heterocyclic groupcontaining 1 to 5 nitrogen atoms, for example, indoline or isoindoline;a partially unsaturated condensed heterocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms; a partially unsaturatedcondensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms; and a saturated condensed heterocyclic group containing1 to 2 oxygen or sulfur atoms.

In one embodiment “heterocycle” refers to a cyclic ring with onenitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with onenitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with twonitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one oxygenand 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one sulfurand 3, 4, 5, 6, 7, or 8 carbon atoms.

Non-limiting examples of “heterocycle” include aziridine, oxirane,thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

Additional non-limiting examples of “heterocycle” include pyrrolidine,3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

Additional non-limiting examples of “heterocycle” includetetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane,and 1,3-oxathiolane.

Additional non-limiting examples of “heterocycle” include piperidine,piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane,1,4-dithiane, morpholine, and thiomorpholine.

Additional non-limiting examples of “heterocycle” include indoline,tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuranwherein the point of attachment for each group is on the heterocyclicring.

For example,

is a “heterocycle” group.

However,

is an “aryl” group.

Non-limiting examples of “heterocycle” also include:

Additional non-limiting examples of “heterocycle” include:

Additional non-limiting examples of “heterocycle” include:

Non-limiting examples of “heterocycle” also include:

Non-limiting examples of “heterocycle” also include:

Additional non-limiting examples of “heterocycle” include:

Additional non-limiting examples of “heterocycle” include:

The term “optionally substituted” denotes the substitution of a groupherein by a moiety including, but not limited to, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ cycloalkenyl, C₁-C₁₂heterocycloalkyl, C₃-C₁₂ heterocycloalkenyl, C₁-C₁₀ alkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, amino, C₁-C₁₀ alkylamino, C₁-C₁₀dialkylamino, arylamino, diarylamino, C₁-C₁₀ alkylsulfonamino,arylsulfonamino, C₁-C₁₀ alkylimino, arylimino, C₁-C₁₀ alkylsulfonimino,arylsulfonimino, hydroxyl, halo, thio, C₁-C₁₀ alkylthio, arylthio,C₁-C₁₀ alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl,amidino, guanidine, ureido, cyano, nitro, azido, acyl, thioacyl,acyloxy, carboxyl, and carboxylic ester.

As used herein, “carbocyclic”, “carbocycle” or “cycloalkyl” includes asaturated or partially unsaturated (i.e., not aromatic) group containingall carbon ring atoms and from 3 to 14 ring carbon atoms (“C₃₋₁₄cycloalkyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms(“C₃₋₁₀ cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 9ring carbon atoms (“C₃₋₉ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ cycloalkyl”). In someembodiments, a cycloalkyl group has 3 to 7 ring carbon atoms (“C₃₋₇cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 4 to 6 ring carbon atoms (“C₄₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Exemplary C₃₋₆ cycloalkyl groupsinclude, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and thelike. Exemplary C₃₋₈ cycloalkyl groups include, without limitation, theaforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), and the like. Exemplary C₃₋₁₀cycloalkyl groups include, without limitation, the aforementioned C₃₋₈cycloalkyl groups as well as cyclononyl (C₉), cyclononenyl (C₉),cyclodecyl (C₁₀), cyclodecenyl (C₁₀), and the like. As the foregoingexamples illustrate, in certain embodiments, the cycloalkyl group can besaturated or can contain one or more carbon-carbon double bonds.

In one embodiment “cycloalkyl” is a C₃-C₈cycloalkyl, C₃-C₇cycloalkyl,C₃-C₆cycloalkyl, C₃-C₈cycloalkyl, C₃-C₄cycloalkyl, C₄-C₈cycloalkyl,C₅-C₈cycloalkyl, or C₆-C₈cycloalkyl.

In one embodiment “cycloalkyl” has three carbons.

In one embodiment “cycloalkyl” has four carbons.

In one embodiment “cycloalkyl” has five carbons.

In one embodiment “cycloalkyl” has six carbons.

In one embodiment “cycloalkyl” has seven carbons.

In one embodiment “cycloalkyl” has eight carbons.

In one embodiment “cycloalkyl” has nine carbons.

In one embodiment “cycloalkyl” has ten carbons.

Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

In another embodiment any suitable group may be present on a“substituted” or “optionally substituted” position if indicated thatforms a stable molecule and meets the desired purpose of the inventionand includes, but is not limited to, e.g., halogen (which canindependently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido;alkanoyl (such as a C₂-C₆ alkanoyl group); carboxamide; alkyl,cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkylincluding those having one or more thioether linkages; alkylsulfinyl;alkylsulfonyl groups including those having one or more sulfonyllinkages; aminoalkyl groups including groups having more than one Natoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ringeither substituted or unsubstituted); arylalkyl having for example, 1 to3 separate or fused rings and from 6 to about 14 or 18 ring carbonatoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, forexample, having 1 to 3 separate or fused rings with benzyloxy being anexemplary arylalkoxy group; or a saturated or partially unsaturatedheterocycle having 1 to 3 separate or fused rings with one or more N, Oor S atoms, or a heteroaryl having 1 to 3 separate or fused rings withone or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl,quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl,thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl,indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, andpyrrolidinyl. Such groups may be further substituted, e.g. with hydroxy,alkyl, alkoxy, halogen and amino. In certain embodiments “optionallysubstituted” includes one or more substituents independently selectedfrom halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH₂, alkylincluding C₁-C₆alkyl, alkenyl including C₂-C₆alkenyl, alkynyl includingC₂-C₆alkynyl, —C₁-C₆alkoxy, alkanoyl including C₂-C₆alkanoyl,C₁-C₆alkylester, (mono- and di-C₁-C₆alkylamino)C₀-C₂alkyl, haloalkylincluding C₁-C₆haloalkyl, hydoxyC₁-C₆alkyl, ester, carbamate, urea,sulfonamide, —C₁-C₆alkyl(heterocyclo), C₁-C₆alkyl(heteroaryl),—C₁-C₆alkyl(C₃-C₇cycloalkyl), 0-C₁-C₆alkyl(C₃-C₇cycloalkyl), B(OH)₂,phosphate, phosphonate and haloalkoxy including C₁-C₆haloalkoxy. In someembodiments, the suitable group present on a “substituted” or“optionally substituted” is divalent including, but not limited to, oxo(═O), ═S, ═CH₂, etc. The suitable group on a “substituted” or “optionalsubstituted” position may be monovalent, divalent, or trivalent suchthat it forms a stable molecule and meets the desired purpose of theinvention.

In one embodiment a group described herein that can be substituted with1, 2, 3, or 4 substituents is substituted with one substituent.

In one embodiment a group described herein that can be substituted with1, 2, 3, or 4 substituents is substituted with two substituents.

In one embodiment a group described herein that can be substituted with1, 2, 3, or 4 substituents is substituted with three substituents.

In one embodiment a group described herein that can be substituted with1, 2, 3, or 4 substituents is substituted with four substituents.

The term “pharmaceutically acceptable” denotes an attribute of amaterial which is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic, and neither biologically nor otherwiseundesirable and is acceptable for veterinary as well as humanpharmaceutical use.

The term “a pharmaceutically acceptable salt” refers to a salt that issuitable for use in contact with the tissues of humans and animals.Examples of suitable salts with inorganic and organic acids are, but arenot limited to, acetic acid, citric acid, formic acid, fumaric acid,hydrochloric acid, lactic acid, maleic acid, malic acid,methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonicacid, succinic acid, sulfuric acid (sulphuric acid), tartaric acid,trifluoroacetic acid and the like. Particular acids are formic acid,trifluoroacetic acid and hydrochloric acid. Specific acids arehydrochloric acid, trifluoroacetic acid and fumaric acid.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like, or using a differentacid that produces the same counterion. Lists of additional suitablesalts may be found, e.g., in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The terms “pharmaceutically acceptable auxiliary substance” refer tocarriers and auxiliary substances such as diluents or excipients thatare compatible with the other ingredients of the formulation.

The term “pharmaceutical composition” encompasses a product comprisingspecified ingredients in pre-determined amounts or proportions, as wellas any product that results, directly or indirectly, from combiningspecified ingredients in specified amounts. Particularly it encompassesa product comprising one or more active ingredients, and an optionalcarrier comprising inert ingredients, as well as any product thatresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The term “as defined herein” and “as described herein” when referring toa variable incorporates by reference the broad definition of thevariable as well as particularly, more particularly and mostparticularly definitions, if any.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

The term “aromatic” denotes the conventional idea of aromaticity asdefined in the literature, in particular in IUPAC—Compendium of ChemicalTerminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). BlackwellScientific Publications, Oxford (1997).

The term “pharmaceutically acceptable excipient” denotes any ingredienthaving no therapeutic activity and being non-toxic such asdisintegrators, binders, fillers, solvents, buffers, tonicity agents,stabilizers, antioxidants, surfactants or lubricants used in formulatingpharmaceutical products.

Whenever a chiral carbon is present in a chemical structure, it isintended that all stereoisomers associated with that chiral carbon areencompassed by the structure as pure stereoisomers as well as mixturesthereof.

Furthermore, the invention includes all optical isomers, i.e.diastereoisomers, diastereomeric mixtures, racemic mixtures, all theircorresponding enantiomers and/or tautomers as well as solvates of thecompounds of formula XV.

The compounds described herein may contain one or more asymmetriccenters and can therefore occur as racemates, racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers and it is intended thatall of the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within this invention.The present invention is meant to encompass all such isomeric forms ofthese compounds. The independent syntheses of these diastereomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography.

In the embodiments, where optically pure enantiomers are provided,optically pure enantiomer means that the compound contains >90% of thedesired isomer by weight, particularly >95% of the desired isomer byweight, or more particularly >99% of the desired isomer by weight, saidweight percent based upon the total weight of the isomer(s) of thecompound. Chirally pure or chirally enriched compounds may be preparedby chirally selective synthesis or by separation of enantiomers. Theseparation of enantiomers may be carried out on the final product oralternatively on a suitable intermediate.

Isotopic Substitution

The present invention includes compounds of Formula I, Formula II,Formula III, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, FormulaXII-a to XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI, andFormula XVII-a to XVII-g with at least one desired isotopic substitutionof an atom, at an amount above the natural abundance of the isotope,i.e., enriched. Isotopes are atoms having the same atomic number butdifferent mass numbers, i.e., the same number of protons but a differentnumber of neutrons.

Examples of isotopes that can be incorporated into compound of theinvention include isotopes of hydrogen, carbon, nitrogen, and oxygensuch as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, and ¹⁷O, ¹⁸O respectively. In onenon-limiting embodiment, isotopically labelled compounds can be used inmetabolic studies (with, for example ¹⁴C), reaction kinetic studies(with, for example ²H or ³H), detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays, or in radioactive treatment of patients. In particular, an ¹⁸Flabeled compound may be particularly desirable for PET or SPECT studies.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95, or 99% or more enriched in an isotope at any locationof interest. In one non-limiting embodiment, deuterium is 90, 95, or 99%enriched at a desired location.

In one non-limiting embodiment, the substitution of a hydrogen atom fora deuterium atom can be provided in any compound of Formula I, FormulaII, Formula III, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII-a to Formula VIII-c, Formula IX, Formula X, Formula XI, FormulaXII-a to XII-c, Formula XIII, Formula XIV, Formula XV, Formula XVI, andFormula XVII-a to XVII-g. In one non-limiting embodiment, thesubstitution of a hydrogen atom for a deuterium atom occurs within oneor more groups selected from the variables described herein. Forexample, when any of the groups are, or contain for example throughsubstitution, methyl, ethyl, or methoxy, the alkyl residue may bedeuterated (in non-limiting embodiments, CDH₂, CD₂H, CD₃, CH₂CD₃,CD₂CD₃, CHDCH₂D, CHDCHD₂, OCDH₂, OCD₂H, or OCD₃, etc.). In certain otherembodiments, when two substitutions are combined to form a cycle, theunsubstituted carbons may be deuterated.

II. Compounds of the Present Invention

The present invention provides compounds of Formula I, Formula II,Formula III, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII-a to VIII-c, Formula IX, Formula X, Formula XI, Formula XII-a toXII-c, Formula XIII, Formula XIV, Formula XVI, and Formula XVII-a toXVII-g, and pharmaceutically acceptable salt thereof. The invention alsoprovides the use of compounds of Formula XV as further described herein.

Compounds of Formula I to Formula XIV

In one aspect, a compound is provided of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula I, a compound is provided selected from:

In another aspect, a compound is provided of Formula II:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula II, a compound is provided selected from:

In another aspect, a compound is provided of Formula III:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula III, a compound is provided selectedfrom:

In some embodiments of Formula III, a compound is provided selectedfrom:

In some embodiments of Formula III, a compound is provided selectedfrom:

In some embodiments of Formula III, a compound is provided selectedfrom:

In some embodiments of Formula III, a compound is provided selectedfrom:

In some embodiments of Formula III, a compound is provided selectedfrom:

In some embodiments of Formula III, a compound is provided selectedfrom:

In some embodiments of Formula III, a compound is provided selectedfrom:

In some embodiments of Formula III, a compound is provided selectedfrom:

In some embodiments of Formula III, a compound is provided selectedfrom:

In another aspect, a compound is provided of Formula IV:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In some embodiments of Formula IV, a compound is provided selected from:

R^(1a) is selected from the group consisting of: —C(═O)—O—C₁₋₆-alkyl;—COOH; and —NO₂.

In another aspect, a compound is provided of Formula V:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula V, a compound is provided selected from:

In another aspect, a compound is provided of Formula VI:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula VI, a compound is provided selected from:

In some embodiments of Formula VI, a compound is provided selected from:

In some embodiments of Formula VI, a compound is provided selected from:

In some embodiments of Formula VI, a compound is provided selected from:

In some embodiments of Formula VI, a compound is provided selected from:

In another aspect, a compound is provided of Formula VII:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula VII, a compound is provided selectedfrom:

In some embodiments of Formula VII, a compound is provided selectedfrom:

In some embodiments of Formula VII, a compound is provided selectedfrom:

In some embodiments of Formula VII, a compound is provided selectedfrom:

In some embodiments of Formula VII, a compound is provided selectedfrom:

In another aspect, a compound is provided of Formula VIII-a, VIII-b, orVIII-c:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula VIII-a, a compound is provided selectedfrom:

In some embodiments of Formula VIII-b, a compound is provided selectedfrom:

In some embodiments of Formula VIII-c, a compound is provided selectedfrom:

In another aspect, a compound is provided of Formula IX:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula IX, a compound is provided selected from:

In some embodiments of Formula IX, a compound is provided selected from:

In another aspect, a compound is provided of Formula X:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula X, a compound is provided selected from:

In some embodiments of Formula X, a compound is provided selected from:

In another aspect, a compound is provided of Formula XI.

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula XI, a compound is provided selected from:

In some embodiments of Formula XI, a compound is provided selected from:

In another aspect, a compound is provided of Formula XII-a, XII-b, orXII-c:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula XII-a, a compound is provided selectedfrom:

In some embodiments of Formula XII-b, a compound is provided selectedfrom:

In some embodiments of Formula XII-c, a compound is provided selectedfrom:

In another aspect, a compound is provided of Formula XIII:

or a pharmaceutically acceptable salt thereof;

wherein all variables are as defined herein.

In some embodiments of Formula XIII, a compound is provided selectedfrom:

In some embodiments of Formula XIII, a compound is provided selectedfrom:

In another aspect, a compound is provided of Formula XIV:

or a pharmaceutically acceptable salt thereof,

wherein all variables are as defined herein.

In some embodiments of Formula XIV, a compound is provided selectedfrom:

In some embodiments of Formula XIV, a compound is provided selectedfrom:

Compounds of Formula XV

In another aspect, the use of a compound of Formula XV, or apharmaceutically acceptable salt thereof, for the treatment of atherapeutic condition which can be treated by modulating the function oractivity of the cereblon containing E3 Ubiquitin Ligase Complex isprovided:

wherein all variables are as defined herein.

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

In some embodiments, the compound of Formula XV for use in the methodsdescribed herein is selected from:

A compound of Formula XV for use in the methods described herein is alsoprovided in the following enumerated embodiments, all of which may beseparately combined.

-   -   E1: One embodiment of the invention provides a compound of        Formula XV, or a pharmaceutically acceptable salt thereof,

-   -   -   wherein        -   Y is NH or CH₂,        -   n is 0 or 1,        -   A is selected from the group consisting of        -   i.) aryl,        -   ii.) aryl substituted by R¹,        -   iii.)heteroaryl, and        -   iv.)heteroaryl substituted by R²;        -   R¹ is selected from the group consisting of        -   i.) —C(═O)—O—C₁₋₆-alkyl,        -   ii.) —COOH,        -   iii.) —NH—C(═O)—C₁₋₆-alkyl,        -   iv.) —NH₂, and        -   v.) —NO₂;        -   R² is selected from the group consisting of        -   i.) —COOH,        -   ii.) —C(═O)—O—C₁₋₆-alkyl,        -   iii.) —NH₂, and        -   NO₂.

    -   E2: The compound of Formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein        -   Y is NH or CH₂,        -   n is 0 or 1,        -   A is selected from the group consisting of        -   i.) aryl,        -   ii.) aryl substituted by R¹,        -   iii.)heteroaryl, and        -   iv.)heteroaryl substituted by R²;        -   R¹ is —NH—C(═O)—C₁₋₆-alkyl; and        -   R² is —C(═O)—O—C₁₋₆-alkyl.

    -   E3: The compound of Formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein        -   A is selected from the group consisting of        -   i.) aryl, in particular phenyl or            1,2,3,4-tetrahydronaphthalenyl,        -   ii.) aryl, in particular phenyl, substituted by R¹, in            particular —NH—C(═O)—C₁₋₆-alkyl,        -   iii.)heteroaryl, in particular benzo[d]thiazolyl,            pyrazolo[1,5-a]pyridinyl, thiazolo[4,5-b]pyridin-2-yl and        -   iv.)heteroaryl, in particular pyridinyl substituted by R²,            in particular —C(═O)—O—C₁₋₆-alkyl.

    -   E4: The compound of Formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is aryl, in        particular phenyl or 1,2,3,4-tetrahydronaphthalenyl.

    -   E5: The compound of Formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is phenyl.

    -   E6: The compound of Formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is        1,2,3,4-tetrahydronaphthalenyl.

    -   E7: The compound of Formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is aryl, in        particular phenyl, substituted by R¹, in particular        —NH—C(═O)—C₁₋₆-alkyl.

    -   E8: The compound of Formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is phenyl,        substituted by —NH—C(═O)—C₁₋₆-alkyl.

    -   E9: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is phenyl,        substituted by —NH—C(═O)—CH₃.

    -   E10: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is heteroaryl, in        particular benzo[d]thiazolyl, pyrazolo[1,5-a]pyridinyl,        thiazolo[4,5-b]pyridin-2-yl.

    -   E11: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is        benzo[d]thiazolyl.

    -   E12: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is        pyrazolo[1,5-a]pyridinyl.

    -   E13: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is        thiazolo[4,5-b]pyridin-2-yl.

    -   E14: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is heteroaryl, in        particular pyridinyl substituted by R², in particular        —C(═O)—O—C₁₋₆-alkyl.

    -   E15: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is pyridinyl        substituted by —C(═O)—O—C₁₋₆-alkyl.

    -   E16: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein A is pyridinyl        substituted by —C(═O)—O—CH₃.

    -   E17: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein Y is NH.

    -   E18: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein Y is CH₂.

    -   E19: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein n is 0.

    -   E20: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, wherein n is 1.

    -   E21: The compound of formula XV, or pharmaceutically acceptable        salts thereof, as described herein, selected from the group        consisting of

-   7-((S)-1,2,3,4-tetrahydronaphthalene-1-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

-   7-benzoyl-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

-   7-(benzo[d]thiazol-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

-   7-(pyrazolo[1,5-a]pyridine-3-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

-   methyl 6-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinate,

-   N-(3-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide,

-   N-(4-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide,

-   7-(thiazolo[4,5-b]pyridin-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

-   7-(benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

-   (R)-7-(benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

-   (S)-7-(benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione,

-   7-(benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.4]nonane-1,3-dione,

-   7-benzoyl-2,7-diazaspiro[4.4]nonane-1,3-dione,

-   methyl 6-(6,8-dioxo-2,7-diazaspiro[4.4]nonan-2-yl)nicotinate, and

-   7-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.4]nonane-1,3-dione.    -   E22: A compound, or pharmaceutically acceptable salts thereof,        having a chemical structure comprising:

P-L-C

-   -   wherein    -   L is a linker group;    -   C is a compound of formula I as described herein,        -   wherein L is chemically linked to C; and    -   P is a protein targeting moiety that binds to a target protein        or a target polypeptide,        -   wherein L is chemically linked to P.    -   E23: The compound of formula P-L-C as described herein, wherein        L is selected from the group consisting of:        -   i) —NHCH₂—(CH₂)₁₋₃₀—C(═O)NH—, in particular            —NHCH₂—(CH₂)₆—C(═O)NH—, and        -   ii) —NH—(CH₂CH₂O)₁₋₂₅—C(═O)NH—.    -   E24: The compound of formula P-L-C as described herein, which is        selected from the group consisting of        -   i) P—NHCH₂—(CH₂)₁₋₃₀—C(═O)NH—C, in particular            P—NHCH₂—(CH₂)₆—C(═O)NH—C, and        -   ii) P—NH—(CH₂CH₂O)₁₋₂₅—C(═O)NH—C.    -   E25: The compound of formula P-L-C as described herein, wherein        P is a BRD4 inhibitor, in particular wherein P is

-   -   E26: A certain embodiment of the invention relates to the        compound of Formula XV as described herein, or a        pharmaceutically acceptable salt thereof, for use as        therapeutically active substance.    -   E27: A certain embodiment of the invention relates to the        compound of Formula XV as described herein, or a        pharmaceutically acceptable salt thereof, for the use in the        therapeutic and/or prophylactic treatment of cancer.    -   E28: A certain embodiment of the invention relates to the        compound of Formula XV as described herein, or a        pharmaceutically acceptable salt thereof, for the manufacture of        a medicament for the therapeutic and/or prophylactic treatment        of cancer.    -   E29: A certain embodiment of the invention relates to a        pharmaceutical composition comprising the compound of Formula XV        as described herein, or a pharmaceutically acceptable salt        thereof, and a pharmaceutically acceptable auxiliary substance.    -   E30: A certain embodiment of the invention relates to a method        for the therapeutic and/or prophylactic treatment of cancer, by        administering the compound of Formula XV as    -   E31: A certain embodiment of the invention relates to the        compound of P-L-C as described herein, or a pharmaceutically        acceptable salt thereof, for use as therapeutically active        substance.    -   E32: A certain embodiment of the invention relates to the        compound of P-L-C as described herein, or a pharmaceutically        acceptable salt thereof, for the use in the therapeutic and/or        prophylactic treatment of cancer.    -   E33: A certain embodiment of the invention relates to the        compound of P-L-C as described herein, or a pharmaceutically        acceptable salt thereof, for the manufacture of a medicament for        the therapeutic and/or prophylactic treatment of cancer.    -   E34: A certain embodiment of the invention relates to a        pharmaceutical composition comprising the compound of P-L-C as        described herein, or a pharmaceutically acceptable salt thereof,        and a pharmaceutically acceptable auxiliary substance, in        particular an inert carrier.    -   E35: A certain embodiment of the invention relates to a method        for the therapeutic and/or prophylactic treatment of cancer, by        administering the compound of P-L-C as described herein, or a        pharmaceutically acceptable salt thereof, to a patient.

Furthermore, the invention includes all optical isomers, i.e.diastereoisomers, diastereomeric mixtures, racemic mixtures, all theircorresponding enantiomers and/or tautomers as well as solvates of thecompounds of formula I.

Salts of Compounds of Formula XV

In cases where the compounds of Formula XV are basic they may beconverted to a corresponding acid addition salt. The conversion isaccomplished by treatment with at least a stoichiometric amount of anappropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, malic acid, malonic acid, succinic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like. Typically, the free base is dissolved in aninert organic solvent such as diethyl ether, ethyl acetate, chloroform,ethanol or methanol and the like, and the acid added in a similarsolvent. The temperature is maintained between 0° C. and 50° C. Theresulting salt precipitates spontaneously or may be brought out ofsolution with a less polar solvent.

Insofar as their preparation is not described in the examples, thecompounds of formula XV or formula P-L-C as well as all intermediateproducts can be prepared according to analogous methods or according tothe methods set forth herein. Starting materials are commerciallyavailable, known in the art or can be prepared by methods known in theart or in analogy thereto.

It will be appreciated that the compounds of general formula XV orformula P-L-C in this invention may be derivatised at functional groupsto provide derivatives which are capable of conversion back to theparent compound in vivo.

Compounds of Formula XVI

In another aspect, a compound of Formula XVI, or a pharmaceuticallyacceptable salt thereof, is provided:

wherein all variables are as defined herein.

In some embodiments, a compound of Formula XVI is provided selectedfrom:

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

In some embodiments of Formula XVI, a compound is provided selectedfrom:

wherein T is

Compound of Formulas XVII-a to XVII-g

In one embodiment, a compound is provided of Formula XVII-a:

wherein all variables are as defined herein.

In some embodiments of Formula XVI or XVII-a,

is selected from:

In one embodiment, a compound is provided of Formula XVII-b:

wherein all variables are as defined herein.

In some embodiments of Formula XVI or XVII-b,

is selected from:

In one embodiment, a compound is provided of Formula XVII-c:

wherein all variables are as defined herein.

In some embodiments of Formula XVI or XVII-d,

is selected from:

In one embodiment, a compound is provided of Formula XVII-d:

wherein all variables are as defined herein.

In some embodiments of Formula XVI or XVII-d,

is selected from:

In one embodiment, a compound is provided of Formula XVII-e:

wherein all variables are as defined herein.

In some embodiments of XVI or XVII-e,

is selected from:

In one embodiment, a compound of Formula XVII-f is provided:

wherein all variables are as defined herein.

In some embodiments of Formula XVI or XVII-f,

is selected from:

In one embodiment, a compound of Formula XVII-g is provided:

wherein all variables are as defined herein.

In some embodiments of Formula XVI or XVII-g,

is selected from:

III. Tail Embodiments

In one embodiment, “Tail” is a moiety selected from Formula T-I, FormulaT-II, Formula T-III, Formula T-IV, Formula T-V, Formula T-VI, andFormula T-VII:

wherein all variables are defined as above.

In an additional embodiment, “Tail” is a moiety selected from FormulaT-VIII, T-IX, and T-X:

wherein all variables are defined as above. In other embodiments ofT-VIII, T-IX and T-X, a carbocyclic ring is used in place of theheterocycle.

The following are non-limiting examples of “Tail” moieties that can beused in this invention. Based on this elaboration, those of skill in theart will understand how to use the full breadth of “Tail” moieties thatwill accomplish the goal of the invention.

As certain non-limiting examples, Formula T-I, Formula T-II, FormulaT-III, Formula T-IV, Formula T-V, Formula T-VI, or Formula T-VIIinclude:

In an additional embodiment “Tail” is selected from:

In an additional embodiment “Tail” is selected from:

Non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, and R²⁴include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³ andR²⁴ include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, andR²⁴ include:

In additional embodiments, “Tail” is an optionally substituted ethyleneglycol having at least 1, at least 2, at least 3, at least 4, at least5, at least 6, at least 7, at least 8, at least 9, at least 10, ethyleneglycol units, or optionally substituted alkyl groups interspersed withoptionally substituted, O, N, S, P or Si atoms. In certain embodiments,“Tail” is flanked, substituted, or interspersed with an aryl, phenyl,benzyl, alkyl, alkylene, or heterocycle group. In certain embodiments,“Tail” may be asymmetric or symmetrical. In some embodiments, “Tail” isa substituted or unsubstituted polyethylene glycol group ranging in sizefrom about 1 to about 12 ethylene glycol units, between 1 and about 10ethylene glycol units, about 2 about 6 ethylene glycol units, betweenabout 2 and 5 ethylene glycol units, between about 2 and 4 ethyleneglycol units. In any of the embodiments of the compounds describedherein, “Tail” group may be any suitable moiety as described herein.

In additional embodiments, the “Tail” is selected from:

—NR⁶¹(CH₂)_(n1)-(lower alkyl)-X²², —NR⁶¹(CH₂)_(n1)-(lower alkoxyl)-X²²,—NR⁶¹(CH₂)_(n1)-(lower alkoxyl)-OCH₂—X²², —NR⁶¹(CH₂)_(n1)-(loweralkoxyl)-(lower alkyl)-OCH₂—X²², —NR⁶¹(CH₂)_(n1)-(cycloalkyl)-(loweralkyl)-OCH₂—X²², —NR⁶¹(CH₂)_(n1)-(heterocycloalkyl)-X²²,—NR⁶¹(CH₂CH₂O)_(n1)-(lower alkyl)-O—CH₂—X²²,—NR⁶¹(CH₂CH₂O)_(n1)-(heterocycloalkyl)-O—CH₂—X²²,—NR⁶¹(CH₂CH₂O)_(n1)-Aryl-O—CH₂—X²²,—NR⁶¹(CH₂CH₂O)_(n1)-(heteroaryl)-O—CH₂—X²²,—NR⁶¹(CH₂CH₂O)_(n1)-(cycloalkyl)-O-(heteroaryl)-O—CH₂—X²²,—NR⁶¹(CH₂CH₂O)_(n1)-(cycloalkyl)-O-Aryl-O—CH₂—X²²,—NR⁶¹(CH₂CH₂O)_(n1)-(lower alkyl)-NH-Aryl-O— CH₂—X²²,—NR⁶¹(CH₂CH₂O)_(n1)-(lower alkyl)-O-Aryl-CH₂—X²²,—NR⁶¹(CH₂CH₂O)_(n1)-cycloalkyl-O-Aryl-X²²,—NR⁶¹(CH₂CH₂O)_(n1)-cycloalkyl-O-heteroaryl-X²²,—NR⁶¹(CH₂CH₂)_(n1)-(cycloalkyl)-O-(heterocycle)-CH₂—X²²,—NR⁶¹(CH₂CH₂)_(n1)-(heterocycle)-(heterocycle)-CH₂—X²², and—NR⁶¹-(heterocycle)-CH₂—X²²;wherein n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; andR⁶¹ is H, methyl, or ethyl.

In additional embodiments, “Tail” is selected from:

—N(R⁶¹)—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—X²²,—O—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—X²²,—O—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OH;—N(R⁶¹)—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OH;—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OH;—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—X²²;—O(CH₂)_(m1)O(CH₂)_(n2)O(CH₂)_(p1)O(CH₂)_(q1)OCH₂—X²²;—O(CH₂)_(m1)O(CH₂)_(n2)O(CH₂)_(p1)O(CH₂)_(q1)OCH₂—X²²; whereinm1, n2, o1, p1, q1, and r1 are independently 1, 2, 3, 4, or 5; andR⁶¹ is H, methyl, or ethyl.

In additional embodiments, “Tail” is selected from:

m1, n2, o1, p1, q2, and r1 are independently 1, 2, 3, 4, or 5.

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

wherein R⁷¹ is —O—, —NH, Nalkyl, heteroaliphatic, aliphatic, or —NMe.

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

In additional embodiments, “Tail” is selected from:

In the above embodiments X²² is selected such that a compoundsufficiently stable or the intended use results.

In additional embodiments, “Tail” is selected from:

In certain embodiments, “Tail” is selected from:

In certain embodiments “Tail” is selected from:

In the above structures

represents

In certain embodiments, “Tail” can be a 4-24 carbon atom linear chains,wherein one or more the carbon atoms in the linear chain can be replacedor substituted with oxygen, nitrogen, amide, fluorinated carbon, etc.,such as the following:

In certain embodiments, “Tail” can be a nonlinear chain, and can be, orinclude, aliphatic or aromatic or heteroaromatic cyclic moieties.

In certain embodiments, “Tail” may include contiguous, partiallycontiguous or non-contiguous ethylene glycol unit groups ranging in sizefrom about 1 to about 12 ethylene glycol units, between 1 and about 10ethylene glycol units, about 2 about 6 ethylene glycol units, betweenabout 2 and 5 ethylene glycol units, between about 2 and 4 ethyleneglycol units, for example, 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12ethylene glycol units.

In certain embodiments, “Tail” may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, or 15 fluorine substituents. In another embodiment“Tail” is perfluorinated. In yet another embodiment “Tail” is apartially or fully fluorinated poly ether. Nonlimiting examples offluorinated “Tail” moieties include:

Representative examples of X²² include:

In certain embodiments, the length can be adjusted as desired or asfound necessary for the desired application.

IV. Methods of Treatment

The compounds of Formula Ia, Formula Ib, Formula II, Formula III a,Formula IIIb, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-tcan be used in an effective amount to treat a host, including a human,in need thereof, optionally in a pharmaceutically acceptable carrier totreat any of the disorders described herein.

The terms “treat”, “treating”, and “treatment”, etc., as used herein,refer to any action providing a benefit to a patient for which thepresent compounds may be administered, including the treatment of anydisease state or condition which is modulated through the protein towhich the present compounds bind. Illustrative non-limiting diseasestates or conditions, including cancer, which may be treated usingcompounds according to the present invention are set forth hereinabove.

The term “disease state or condition” when used in connection with aFormula Ia, Formula Ib, Formula II, Formula III a, Formula IIIb, FormulaIV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX,Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, FormulaXV, Formula XIV-a to XIV-x, or Formula XV-a to XV-t compound forexample, refers to any therapeutic indication which can be treated bydecreasing the activity of cereblon or a cereblon-containing E3 Ligase.Nonlimiting examples of uses for cereblon binders are multiple myeloma,a hematological disorder such as myelodysplastic syndrome, cancer,tumor, abnormal cellular proliferation, HIV/AIDS, HBV, HCV, hepatitis,Crohn's disease, sarcoidosis, graft-versus-host disease, rheumatoidarthritis, Behcet's disease, tuberculosis, and myelofibrosis. Otherindications include a myelo- or lymphoproliferative disorder such as B-or T-cell lymphomas, Waldenstrom's macroglobulinemia, Wiskott-Aldrichsyndrome, or a post-transplant lymphoproliferative disorder; an immunedisorder, including autoimmune disorders such as Addison disease, Celiacdisease, dermatomyositis, Graves disease, thyroiditis, multiplesclerosis, pernicious anemia, arthritis, and in particular rheumatoidarthritis, lupus, or type I diabetes; a disease of cardiologicmalfunction, including hypercholesterolemia; an infectious disease,including viral and/or bacterial infection, as described generallyherein; an inflammatory condition, including asthma, chronic pepticulcers, tuberculosis, rheumatoid arthritis, periodontitis and ulcerativecolitis.

In certain embodiments, the present invention provides for administeringa compound of Formula Ia, Formula Ib, Formula II, Formula III a, FormulaIIIb, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, FormulaXIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-t to apatient, for example, a human, having an infectious disease, wherein thetherapy targets a protein of the infectious agent, optionally incombination with another bioactive agent. The disease state or conditionmay be a disease caused by a microbial agent or other exogenous agentsuch as a virus (as non-limiting examples, HIV, HBV, HCV, HSV, HPV, RSV,CMV, Ebola, Flavivirus, Pestivirus, Rotavirus, Influenza, Coronavirus,EBV, viral pneumonia, drug-resistant viruses, Bird flu, RNA virus, DNAvirus, adenovirus, poxvirus, Picornavirus, Togavirus, Orthomyxovirus,Retrovirus or Hepadnovirus), bacteria (Gram-negative, Gram-positive,fungus, protozoa, helminth, worms, prion, parasite, or other microbe ormay be a disease state, which is caused by overexpression of a protein,which leads to a disease state and/or condition.

In certain embodiments, the condition treated with a compound of thepresent invention is a disorder related to abnormal cellularproliferation. Abnormal cellular proliferation, notablyhyperproliferation, can occur as a result of a wide variety of factors,including genetic mutation, infection, exposure to toxins, autoimmunedisorders, and benign or malignant tumor induction.

There are a number of skin disorders associated with cellularhyperproliferation. Psoriasis, for example, is a benign disease of humanskin generally characterized by plaques covered by thickened scales. Thedisease is caused by increased proliferation of epidermal cells ofunknown cause. Chronic eczema is also associated with significanthyperproliferation of the epidermis. Other diseases caused byhyperproliferation of skin cells include atopic dermatitis, lichenplanus, warts, pemphigus vulgaris, actinic keratosis, basal cellcarcinoma and squamous cell carcinoma.

Other hyperproliferative cell disorders include blood vesselproliferation disorders, fibrotic disorders, autoimmune disorders,graft-versus-host rejection, tumors and cancers.

Blood vessel proliferative disorders include angiogenic and vasculogenicdisorders. Proliferation of smooth muscle cells in the course ofdevelopment of plaques in vascular tissue cause, for example,restenosis, retinopathies and atherosclerosis. Both cell migration andcell proliferation play a role in the formation of atheroscleroticlesions.

Fibrotic disorders are often due to the abnormal formation of anextracellular matrix. Examples of fibrotic disorders include hepaticcirrhosis and mesangial proliferative cell disorders. Hepatic cirrhosisis characterized by the increase in extracellular matrix constituentsresulting in the formation of a hepatic scar. Hepatic cirrhosis cancause diseases such as cirrhosis of the liver. An increasedextracellular matrix resulting in a hepatic scar can also be caused byviral infection such as hepatitis. Lipocytes appear to play a major rolein hepatic cirrhosis.

Mesangial disorders are brought about by abnormal proliferation ofmesangial cells. Mesangial hyperproliferative cell disorders includevarious human renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic micro-angiopathysyndromes, transplant rejection, and glomerulopathies.

Another disease with a proliferative component is rheumatoid arthritis.Rheumatoid arthritis is generally considered an autoimmune disease thatis thought to be associated with activity of autoreactive T cells, andto be caused by autoantibodies produced against collagen and IgE.

Other disorders that can include an abnormal cellular proliferativecomponent include Bechet's syndrome, acute respiratory distress syndrome(ARDS), ischemic heart disease, post-dialysis syndrome, leukemia,acquired immune deficiency syndrome, vasculitis, lipid histiocytosis,septic shock and inflammation in general.

Cutaneous contact hypersensitivity and asthma are just two examples ofimmune responses that can be associated with significant morbidity.Others include atopic dermatitis, eczema, Sjogren's Syndrome, includingkeratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopeciaareata, allergic responses due to arthropod bite reactions, Crohn'sdisease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis,ulcerative colitis, cutaneous lupus erythematosus, scleroderma,vaginitis, proctitis, and drug eruptions. These conditions may result inany one or more of the following symptoms or signs: itching, swelling,redness, blisters, crusting, ulceration, pain, scaling, cracking, hairloss, scarring, or oozing of fluid involving the skin, eye, or mucosalmembranes.

In atopic dermatitis, and eczema in general, immunologically mediatedleukocyte infiltration (particularly infiltration of mononuclear cells,lymphocytes, neutrophils, and eosinophils) into the skin importantlycontributes to the pathogenesis of these diseases. Chronic eczema alsois associated with significant hyperproliferation of the epidermis.Immunologically mediated leukocyte infiltration also occurs at sitesother than the skin, such as in the airways in asthma and in the tearproducing gland of the eye in keratoconjunctivitis sicca.

In one non-limiting embodiment compounds of the present invention areused as topical agents in treating contact dermatitis, atopicdermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome,including keratoconjunctivitis sicca secondary to Sjogren's Syndrome,alopecia areata, allergic responses due to arthropod bite reactions,Crohn's disease, aphthous ulcer, iritis, conjunctivitis,keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma,cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, anddrug eruptions. The novel method may also be useful in reducing theinfiltration of skin by malignant leukocytes in diseases such as mycosisfungoides. These compounds can also be used to treat anaqueous-deficient dry eye state (such as immune mediatedkeratoconjunctivitis) in a patient suffering therefrom, by administeringthe compound topically to the eye.

Disease states of conditions which may be treated using compoundsaccording to the present invention include, for example, asthma,autoimmune diseases such as multiple sclerosis, various cancers,ciliopathies, cleft palate, diabetes, heart disease, hypertension,inflammatory bowel disease, mental retardation, mood disorder, obesity,refractive error, infertility, Angelman syndrome, Canavan disease,Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchennemuscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter'ssyndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease1 (PKD1) or 2 (PKD2) Prader-Willi syndrome, Sickle-cell disease,Tay-Sachs disease, Turner syndrome.

Further disease states or conditions which may be treated by compoundsaccording to the present invention include Alzheimer's disease,Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa,Anxiety disorder, Atherosclerosis, Attention deficit hyperactivitydisorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronicobstructive pulmonary disease, Crohn's disease, Coronary heart disease,Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type2, Epilepsy, Guillain-Barre syndrome, Irritable bowel syndrome, Lupus,Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity,Obsessive-compulsive disorder, Panic disorder, Parkinson's disease,Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke,Thromboangiitis obliterans, Tourette syndrome, Vasculitis.

Still additional disease states or conditions which can be treated bycompounds according to the present invention include aceruloplasminemia,Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher diseasetype 2, acute intermittent porphyria, Canavan disease, AdenomatousPolyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyasedeficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-Dporphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease,Alkaptonuric ochronosis, alpha 1-antitrypsin deficiency, alpha-1proteinase inhibitor, emphysema, amyotrophic lateral sclerosis Alströmsyndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratasedeficiency, Anderson-Fabry disease, androgen insensitivity syndrome,Anemia Angiokeratoma Corporis Diffusum, Angiomatosis retinae (vonHippel-Lindau disease) Apert syndrome, Arachnodactyly (Marfan syndrome),Stickler syndrome, Arthrochalasis multiplex congenital (Ehlers-Danlossyndrome #arthrochalasia type) ataxia telangiectasia, Rett syndrome,primary pulmonary hypertension, Sandhoff disease, neurofibromatosis typeII, Beare-Stevenson cutis gyrata syndrome, Mediterranean fever,familial, Benjamin syndrome, beta-thalassemia, Bilateral AcousticNeurofibromatosis (neurofibromatosis type II), factor V Leidenthrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloomsyndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome(Turner syndrome), Bourneville disease (tuberous sclerosis), priondisease, Birt-Hogg-Dube syndrome, Brittle bone disease (osteogenesisimperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome),Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinalmuscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoproteinlipase deficiency), CGD Chronic granulomatous disorder, Campomelicdysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cridu chat, CAVD (congenital absence of the vas deferens), Caylorcardiofacial syndrome (CBAVD), CEP (congenital erythropoieticporphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophysyndrome (achondroplasia), otospondylomegaepiphyseal dysplasia,Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome,Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome,(familial adenomatous polyposis), Congenital erythropoietic porphyria,Congenital heart disease, Methemoglobinemia/Congenitalmethaemoglobinaemia, achondroplasia, X-linked sideroblastic anemia,Connective tissue disease, Conotruncal anomaly face syndrome, Cooley'sAnemia (beta-thalassemia), Copper storage disease (Wilson's disease),Copper transport disease (Menkes disease), hereditary coproporphyria,Cowden syndrome, Craniofacial dysarthrosis (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowdensyndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy),Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy,Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nervediseases including de Grouchy syndrome and Dejerine-Sottas syndrome,developmental disabilities, distal spinal muscular atrophy, type V,androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbedisease), Di George's syndrome, Dihydrotestosterone receptor deficiency,androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoieticprotoporphyria Erythroid 5-aminolevulinate synthetase deficiency,Erythropoietic porphyria, erythropoietic protoporphyria, erythropoieticuroporphyria, Friedreich's ataxia-familial paroxysmal polyserositis,porphyria cutanea tarda, familial pressure sensitive neuropathy, primarypulmonary hypertension (PPH), Fibrocystic disease of the pancreas,fragile X syndrome, galactosemia, genetic brain disorders, Giant cellhepatitis (Neonatal hemochromatosis), Gronblad-Strandberg syndrome(pseudoxanthoma elasticum), Gunther disease (congenital erythropoieticporphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia,hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia,Hypochromic anemia, Immune system disorders, including X-linked severecombined immunodeficiency, Insley-Astley syndrome, Jackson-Weisssyndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weisssyndrome, Kidney diseases, including hyperoxaluria, Klinefelter'ssyndrome, Kniest dysplasia, Lacunar dementia, Langer-Saldinoachondrogenesis, ataxia telangiectasia, Lynch syndrome,Lysyl-hydroxylase deficiency, Machado-Joseph disease, Metabolicdisorders, including Kniest dysplasia, Marfan syndrome, Movementdisorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome,Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeneychondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffersyndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystickidney disease, polyostotic fibrous dysplasia (McCune-Albrightsyndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome,hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome),primary pulmonary hypertension, primary senile degenerative dementia,prion disease, progeria (Hutchinson Gilford Progeria Syndrome),progressive chorea, chronic hereditary (Huntington) (Huntington'sdisease), progressive muscular atrophy, spinal muscular atrophy,propionic acidemia, protoporphyria, proximal myotonic dystrophy,pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb(retinoblastoma), Recklinghausen disease (neurofibromatosis type I),Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rettsyndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levysyndrome, severe achondroplasia with developmental delay and acanthosisnigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, andadrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis),SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SEDStrudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome,Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South-Africangenetic porphyria (variegate porphyria), infantile-onset ascendinghereditary spastic paralysis, Speech and communication disorders,sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Sticklersyndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterindeficiency, beta-thalassemia, Thyroid disease, Tomaculous neuropathy(hereditary neuropathy with liability to pressure palsies), TreacherCollins syndrome, Triplo X syndrome (triple X syndrome), Trisomy 21(Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease),Vision impairment and blindness (Alstrom syndrome), Vrolik disease,Waardenburg syndrome, Warburg Sjo Fledelius Syndrome,Weissenbacher-Zweymüller syndrome, Wolf-Hirschhorn syndrome, WolffPeriodic disease, Weissenbacher-Zweymüller syndrome and Xerodermapigmentosum, among others.

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue thatgrows by cellular proliferation, often more rapidly than normal andcontinues to grow after the stimuli that initiated the new growth cease.Malignant neoplasms show partial or complete lack of structuralorganization and functional coordination with the normal tissue and mostinvade surrounding tissues, metastasize to several sites, and are likelyto recur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors.

Exemplary cancers which may be treated by the present compounds eitheralone or in combination with at least one additional anti-cancer agentinclude squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma,hepatocellular carcinomas, and renal cell carcinomas, cancer of thebladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver,lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benignand malignant lymphomas, particularly Burkitt's lymphoma andNon-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using compounds according to the present invention include, forexample, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineagelymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cellLeukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, BurkittsLymphoma, B-cell ALL, Philadelphia chromosome positive ALL andPhiladelphia chromosome positive CML.

Additional cancers which may be treated using the disclosed compoundsaccording to the present invention include, for example, acutegranulocytic leukemia, acute lymphocytic leukemia (ALL), acutemyelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenalcancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma,angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Celllymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrowcancer, bowel cancer, brain cancer, brain stem glioma, breast cancer,triple (estrogen, progesterone and HER-2) negative breast cancer, doublenegative breast cancer (two of estrogen, progesterone and HER-2 arenegative), single negative (one of estrogen, progesterone and HER-2 isnegative), estrogen-receptor positive, HER2-negative breast cancer,estrogen receptor-negative breast cancer, estrogen receptor positivebreast cancer, metastatic breast cancer, luminal A breast cancer,luminal B breast cancer, Her2-negative breast cancer, HER2-positive ornegative breast cancer, progesterone receptor-negative breast cancer,progesterone receptor-positive breast cancer, recurrent breast cancer,carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma,chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma,cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ(DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophagealcancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer,fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer,gastrointestinal cancer, gastrointestinal carcinoid cancer,gastrointestinal stromal tumors (GIST), germ cell tumor glioblastomamultiforme (GBM), glioma, hairy cell leukemia, head and neck cancer,hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer,infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma(ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepaticbile duct cancer, invasive/infiltrating breast cancer, Islet cellcancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer,leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer,liposarcoma, liver cancer, lobular carcinoma in situ, low-gradeastrocytoma, lung cancer, lymph node cancer, lymphoma, male breastcancer, medullary carcinoma, medulloblastoma, melanoma, meningioma,Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous,mesothelioma metastatic breast cancer, metastatic melanoma metastaticsquamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancermucinous carcinoma, mucosal melanoma, multiple myeloma, MycosisFungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngealcancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs),non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cellcancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer,oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma.

In one embodiment the cancer is NUT midline cardinioma.

In one embodiment the cancer is adenoid cystic carcinoma.

The term “bioactive agent” is used to describe an agent, other than acompound according to the present invention, which is used incombination with the present compounds as an agent with biologicalactivity to assist in effecting an intended therapy, inhibition and/orprevention/prophylaxis for which the present compounds are used.Preferred bioactive agents for use herein include those agents whichhave pharmacological activity similar to that for which the presentcompounds are used or administered and include for example, anti-canceragents, antiviral agents, especially including anti-HIV agents andanti-HCV agents, antimicrobial agents, antifungal agents, etc.

In one embodiment, a method is provided for treating multiple myelomacomprising administering to a patient an effective amount of a compounddescribed herein, or a pharmaceutically acceptable salt, isotopicanalog, or prodrug thereof, optionally in a pharmaceutically acceptablecarrier to form a composition. In another embodiment, a compounddescribed herein or a pharmaceutically acceptable salt, isotopic analog,or prodrug thereof, optionally in a pharmaceutically acceptable carrierto form a composition, for use in a method of treating multiple myeloma,wherein the method comprises administering the compound to a patient.

In one embodiment, a method is provided for managing the progression ofmultiple myeloma comprising administering to a patient an effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition. In anotherembodiment, a compound described herein, or a pharmaceuticallyacceptable salt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, for use in amethod of managing the progression of multiple myeloma, wherein themethod comprises administering the compound to a patient.

In one embodiment, a method is provided for inducing a therapeuticresponse as assessed by the International Uniform Response Criteria(IURC) for Multiple Myeloma (described in Durie B. G. M; et al.“International uniform response criteria for multiple myeloma. Leukemia2006, 10(10):1-7) in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided to achieve a stringentcomplete response, complete response, or very good partial response, asassessed by the IURC for Multiple Myeloma in a patient having multiplemyeloma comprising administering to the patient an effective amount of acompound described herein, or a pharmaceutically acceptable salt,isotopic analog, or prodrug thereof, optionally in a pharmaceuticallyacceptable carrier to form a composition.

In another embodiment, a method is provided to achieve an increase inoverall survival, progression-free survival, event-free survival, timeto process, or disease-free survival in a patient having multiplemyeloma comprising administering to the patient an effective amount of acompound described herein, or a pharmaceutically acceptable salt,isotopic analog, or prodrug thereof, optionally in a pharmaceuticallyacceptable carrier to form a composition.

In another embodiment, a method is provided to achieve an increase inoverall survival in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided to achieve an increase inprogression-free survival in a patient having multiple myelomacomprising administering to the patient an effective amount of acompound described herein, or a pharmaceutically acceptable salt,isotopic analog, or prodrug thereof, optionally in a pharmaceuticallyacceptable carrier to form a composition.

In another embodiment, a method is provided to achieve an increase inevent-free survival in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided to achieve an increase intime to progression in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided to achieve an increase indisease-free survival in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

Methods are also provided to treat patients who have been previouslytreated for multiple myeloma but are non-responsive to standardtherapies in addition to those who have not been previously treated.Additional methods are provided to treat patients who have undergonesurgery in an attempt to treat multiple myeloma in addition to those whohave not undergone surgery. Methods are also provided to treat patientswho have previously undergone transplant therapy in addition to thosewho have not.

The compounds described herein may be used in the treatment ormanagement of multiple myeloma that is relapsed, refractory, orresistant. In some embodiments, the multiple myeloma is primary,secondary, tertiary, quadruply or quintuply relapsed. In one embodiment,the compounds described herein may be used to reduce, maintain, oreliminate minimal residual disease (MRD).

The types of multiple myeloma that may be treated with the compoundsdescribed herein include, but are not limited to: monoclonal gammopathyof undetermined significance (MGUS); low risk, intermediate risk, orhigh risk multiple myeloma; newly diagnosed multiple myeloma, includinglow risk, intermediate risk, or high risk newly diagnosed multiplemyeloma); transplant eligible and transplant ineligible multiplemyeloma; smoldering (indolent) multiple myeloma (including low risk,intermediate risk, or high risk smoldering multiple myeloma); activemultiple myeloma; solitary plasmocytoma; plasma cell leukemia; centralnervous system multiple myeloma; light chain myeloma; non-secretorymyeloma; Immunoglobulin D myeloma; and Immunoglobulin E myeloma.

In some embodiments, the compounds described herein may be used in thetreatment or management of multiple myeloma characterized by geneticabnormalities, for example but not limited to: Cyclin D translocations(for example, t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); ort(6;20);); MMSET translocations (for example t(4;14)(p16;q32); MAFtranslocations (for example t(14;16)(q32;a32); t(20;22);t(16;22)(q11;q13); or t(14;20)(q32;q11); or other chromosome factors(for example deletion of 17p13 or chromosome 13; del(17/17p),nonhyperdiploidy, and gain (1q)).

In one embodiment, a method is provided for treating or managingmultiple myeloma comprising administering to a patient an effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, as inductiontherapy.

In one embodiment, a method is provided for treating or managingmultiple myeloma comprising administering to a patient an effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, asconsolidation therapy.

In one embodiment, a method is provided for treating or managingmultiple myeloma comprising administering to a patient an effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, asmaintenance therapy.

In one embodiment, the multiple myeloma is plasma cell leukemia.

In one embodiment, the multiple myeloma is high risk multiple myeloma.In some embodiments, the high risk multiple myeloma is relapsed orrefractory. In one embodiment, the high risk multiple myeloma hasrelapsed within 12 months of the first treatment. In another embodiment,the high risk multiple myeloma is characterized by geneticabnormalities, for example, one or more of del(17/17p) andt(14;16)(q32;q32). In some embodiments, the high risk multiple myelomais relapsed or refractory to one, two or three previous treatments.

In one embodiment, the multiple myeloma has a p53 mutation. In oneembodiment, the p53 mutation is a Q331 mutation. In one embodiment, thep53 mutation is a R273H mutation. In one embodiment, the p53 mutation isa K132 mutation. In one embodiment, the p53 mutation is a K132Nmutation. In one embodiment, the p53 mutation is a R337 mutation. In oneembodiment, the p53 mutation is a R337L mutation. In one embodiment, thep53 mutation is a W146 mutation. In one embodiment, the p53 mutation isa S261 mutation. In one embodiment, the p53 mutation is a S261Tmutation. In one embodiment, the p53 mutation is a E286 mutation. In oneembodiment, the p53 mutation is a E286K mutation. In one embodiment, thep53 mutation is a R175 mutation. In one embodiment, the p53 mutation isa R175H mutation. In one embodiment, the p53 mutation is a E258mutation. In one embodiment, the p53 mutation is a E258K mutation. Inone embodiment, the p53 mutation is a A161 mutation. In one embodiment,the p53 mutation is a A161T mutation.

In one embodiment, the multiple myeloma has a homozygous deletion ofp53. In one embodiment, the multiple myeloma has a homozygous deletionof wild-type p53. In one embodiment, the multiple myeloma has wild-typep53.

In one embodiment, the multiple myeloma shows activation of one or moreoncogenic drivers. In one embodiment, the one or more oncogenic driversare selected from the group consisting of C-MAF, MAFB, FGFR3, MMset,Cyclin D1, and Cyclin D. In one embodiment, the multiple myeloma showsactivation of C-MAF. In one embodiment, the multiple myeloma showsactivation of MAFB. In one embodiment, the multiple myeloma showsactivation of FGFR3 and MMset. In one embodiment, the multiple myelomashows activation of C-MAF, FGFR3, and MMset. In one embodiment, themultiple myeloma shows activation of Cyclin D1. In one embodiment, themultiple myeloma shows activation of MAFB and Cyclin D1. In oneembodiment, the multiple myeloma shows activation of Cyclin D.

In one embodiment, the multiple myeloma has one or more chromosomaltranslocations. In one embodiment, the chromosomal translocation ist(14;16). In one embodiment, the chromosomal translocation is t(14;20).In one embodiment, the chromosomal translocation is t(4; 14). In oneembodiment, the chromosomal translocations are t(4;14) and t(14;16). Inone embodiment, the chromosomal translocation is t(11;14). In oneembodiment, the chromosomal translocation is t(6;20). In one embodiment,the chromosomal translocation is t(20;22). In one embodiment, thechromosomal translocations are t(6;20) and t(20;22). In one embodiment,the chromosomal translocation is t(16;22). In one embodiment, thechromosomal translocations are t(14;16) and t(16;22). In one embodiment,the chromosomal translocations are t(14;20) and t(11;14).

In one embodiment, the multiple myeloma has a Q331 p53 mutation,activation of C-MAF, and a chromosomal translocation at t(14; 16). Inone embodiment, the multiple myeloma has homozygous deletion of p53,activation of C-MAF, and a chromosomal translocation at t(14; 16). Inone embodiment, the multiple myeloma has a K132N p53 mutation,activation of MAFB, and a chromosomal translocation at t(14;20). In oneembodiment, the multiple myeloma has wild type p53, activation of FGFR3and MMset, and a chromosomal translocation at t(4; 14). In oneembodiment, the multiple myeloma has wild type p53, activation of C-MAF,and a chromosomal translocation at t(14;16). In one embodiment, themultiple myeloma has homozygous deletion of p53, activation of FGFR3,MMset, and C-MAF, and chromosomal translocations at t(4;14) andt(14;16). In one embodiment, the multiple myeloma has homozygousdeletion of p53, activation of Cyclin D1, and a chromosomaltranslocation at t(11;14). In one embodiment, the multiple myeloma has aR337L p53 mutation, activation of Cyclin D1, and a chromosomaltranslocation at t(11;14). In one embodiment, the multiple myeloma has aW146 p53 mutation, activation of FGFR3 and MMset, and a chromosomaltranslocation at t(4; 14). In one embodiment, the multiple myeloma has aS261T p53 mutation, activation of MAFB, and chromosomal translocationsat t(6;20) and t(20;22). In one embodiment, the multiple myeloma has aE286K p53 mutation, by activation of FGFR3 and MMset, and a chromosomaltranslocation at t(4; 14). In one embodiment, the multiple myeloma has aR175H p53 mutation, activation of FGFR3 and MMset, and a chromosomaltranslocation at t(4; 14). In one embodiment, the multiple myeloma has aE258K p53 mutation, activation of C-MAF, and chromosomal translocationsat t(14;16) and t(16;22). In one embodiment, the multiple myeloma haswild type p53, activation of MAFB and Cyclin D1, and chromosomaltranslocations at t(14;20) and t(11;14). In one embodiment, the multiplemyeloma has a A161T p53 mutation, activation of Cyclin D, and achromosomal translocation at t(11;14).

In some embodiments, the multiple myeloma is transplant eligible newlydiagnosed multiple myeloma. In other embodiments, the multiple myelomais transplant ineligible newly diagnosed multiple myeloma.

In some embodiments, the multiple myeloma shows early progression (forexample less than 12 months) following initial treatment. In otherembodiments, the multiple myeloma shows early progression (for exampleless than 12 months) following autologous stem cell transplant. Inanother embodiment, the multiple myeloma is refractory to lenalidomide.In another embodiment, the multiple myeloma is refractory topomalidomide. In some such embodiments, the multiple myeloma ispredicted to be refractory to pomalidomide (for example, by molecularcharacterization). In another embodiment, the multiple myeloma isrelapsed or refractory to 3 or more treatments and was exposed to aproteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib,oprozomib, or marizomib) and an immunomodulatory compound (for examplethalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), ordouble refractory to a proteasome inhibitor and an immunomodulatorycompound. In still other embodiments, the multiple myeloma is relapsedor refractory to 3 or more prior therapies, including for example, aCD38 monoclonal antibody (CD38 mAb, for example, daratumumab orisatuximab), a proteasome inhibitor (for example, bortezomib,carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound(for example thalidomide, lenalidomide, pomalidomide, iberdomide, oravadomide) or double refractory to a proteasome inhibitor orimmunomodulatory compound and a CD38 mAb. In still other embodiments,the multiple myeloma is triple refractory, for example, the multiplemyeloma is refractory to a proteasome inhibitor (for example,bortezomib, carfilzomib, ixazomib, oprozomib or marizomib), animmunomodulatory compound (for example thalidomide, lenalidomide,pomalidomide, iberdomide, or avadomide), and one other active agent, asdescribed herein.

In one embodiment, a method is provided for treating or managingrelapsed or refractory multiple myeloma in patients with impaired renalfunction or a symptom thereof comprising administering to a patient aneffective amount of a compound described herein, or a pharmaceuticallyacceptable salt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition.

In another embodiment, a method is provided for treating or managingrelapsed or refractory multiple myeloma in frail patients comprisingadministering to a patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition, wherein the frail patient is characterized byineligibility for induction therapy or intolerance to dexamethasonetreatment. In other embodiments, the frail patient is elderly, forexample, older than 65 years old.

In another embodiment, a method is provided for treating or managingfourth line relapsed or refractory multiple myeloma comprisingadministering to a patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided for treating or managingnewly diagnosed, transplant-ineligible multiple myeloma comprisingadministering to a patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition.

In another embodiment, a method is provided for treating or managingnewly diagnosed, transplant-ineligible multiple myeloma comprisingadministering to a patient an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, isotopic analog, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition, as maintenance therapy after another therapy ortransplant.

In another embodiment, a method is provided for treating or managinghigh risk multiple myeloma that is relapsed or refractory to one, two,or three previous treatments comprising administering to a patient aneffective amount of a compound described herein, or a pharmaceuticallyacceptable salt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition.

In some embodiments, the patient to be treated by one of the compoundsdescribed herein has not be treated with multiple myeloma therapy priorto administration. In some embodiments, the patient to be treated by oneof the compounds described herein has been treated by multiple myelomatherapy prior to administration. In some embodiments, the patient to betreated by one of the compounds described herein has developed drugresistant to the multiple myeloma therapy.

In some embodiments, the patient to be treated by one of the compoundsdescribed herein has developed resistance to one, two, or three multiplemyeloma therapies, wherein the therapies are selected from a CD38antibody (CD38 mAB, for example, daratumumab or isatuximab), aproteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, ormarizomib), and an immunomodulatory compound (for example thalidomide,lenalidomide, pomalidomide, iberdomide, or avodomide).

The compounds described herein can be used to treat a patient regardlessof patient's age. In some embodiments, the subject is 18 years or older.In other embodiments, the subject is more than 18, 25, 35, 40, 45, 50,55, 60, 65, or 70 years old. In other embodiments, the patient is lessthan 65 years old. In other embodiments, the patient is more than 65years old. In one embodiment, the patient is an elderly multiple myelomapatient, such as a patient older than 65 years old. In one embodiment,the patient is an elderly multiple myeloma patient, such as a patientolder than 75 years old.

V. Combination Therapy

The compounds of Formula Ia, Formula Ib, Formula II, Formula III a,Formula IIIb, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-tcan be used in an effective amount alone or in combination to treat ahost such as a human with a disorder as described herein.

The disclosed compounds described herein can be used in an effectiveamount alone or in combination with another compound of the presentinvention or another bioactive agent to treat a host such as a humanwith a disorder as described herein.

The term “bioactive agent” is used to describe an agent, other than theselected compound according to the present invention, which can be usedin combination or alternation with a compound of the present inventionto achieve a desired result of therapy. In one embodiment, the compoundof the present invention and the bioactive agent are administered in amanner that they are active in vivo during overlapping time periods, forexample, have time-period overlapping Cmax, Tmax, AUC or otherpharmacokinetic parameter. In another embodiment, the compound of thepresent invention and the bioactive agent are administered to a host inneed thereof that do not have overlapping pharmacokinetic parameter,however, one has a therapeutic impact on the therapeutic efficacy of theother.

In one aspect of this embodiment, the bioactive agent is an immunemodulator, including but not limited to a checkpoint inhibitor,including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor,PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor,V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, smallmolecule, peptide, nucleotide, or other inhibitor. In certain aspects,the immune modulator is an antibody, such as a monoclonal antibody.

VI. Pharmaceutical Compositions

The compounds of Formula Ia, Formula Ib, Formula II, Formula III a,Formula IIIb, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-tas disclosed herein can be administered as the neat chemical, but aremore typically administered as a pharmaceutical composition, thatincludes an effective amount for a host, typically a human, in need ofsuch treatment for any of the disorders described herein. Accordingly,the disclosure provides pharmaceutical compositions comprising aneffective amount of compound or pharmaceutically acceptable salttogether with at least one pharmaceutically acceptable carrier for anyof the uses described herein. The pharmaceutical composition may containa compound or salt as the only active agent, or, in an alternativeembodiment, the compound and at least one additional active agent.

In certain embodiments the pharmaceutical composition is in a dosageform that contains from about 0.1 mg to about 2000 mg, from about 10 mgto about 1000 mg, from about 100 mg to about 800 mg, or from about 200mg to about 600 mg of the active compound and optionally from about 0.1mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100mg to about 800 mg, or from about 200 mg to about 600 mg of anadditional active agent in a unit dosage form. Examples are dosage formswith at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600,700, or 750 mg of active compound, or its salt. The pharmaceuticalcomposition may also include a molar ratio of the active compound and anadditional active agent. For example the pharmaceutical composition maycontain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 orfrom about 1.5:1 to about 4:1 of an anti-inflammatory orimmunosuppressing agent. Compounds disclosed herein may be administeredorally, topically, parenterally, by inhalation or spray, sublingually,via implant, including ocular implant, transdermally, via buccaladministration, rectally, as an ophthalmic solution, injection,including ocular injection, intraveneous, intra-aortal, intracranial,subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, orrectal or by other means, in dosage unit formulations containingconventional pharmaceutically acceptable carriers. For ocular delivery,the compound can be administered, as desired, for example, viaintravitreal, intrastromal, intracameral, sub-tenon, sub-retinal,retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival,episcleral, periocular, transscleral, retrobulbar, posteriorjuxtascleral, circumcorneal, or tear duct injections, or through amucus, mucin, or a mucosal barrier, in an immediate or controlledrelease fashion or via an ocular device.

The pharmaceutical composition may be formulated as any pharmaceuticallyuseful form, e.g., as an aerosol, a cream, a gel, a pill, an injectionor infusion solution, a capsule, a tablet, a syrup, a transdermal patch,a subcutaneous patch, a dry powder, an inhalation formulation, in amedical device, suppository, buccal, or sublingual formulation,parenteral formulation, or an ophthalmic solution. Some dosage forms,such as tablets and capsules, are subdivided into suitably sized unitdoses containing appropriate quantities of the active components, e.g.,an effective amount to achieve the desired purpose.

Carriers include excipients and diluents and must be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the patient being treated. The carrier can be inert orit can possess pharmaceutical benefits of its own. The amount of carrieremployed in conjunction with the compound is sufficient to provide apractical quantity of material for administration per unit dose of thecompound.

Classes of carriers include, but are not limited to binders, bufferingagents, coloring agents, diluents, disintegrants, emulsifiers,flavorants, glidents, lubricants, preservatives, stabilizers,surfactants, tableting agents, and wetting agents. Some carriers may belisted in more than one class, for example vegetable oil may be used asa lubricant in some formulations and a diluent in others. Exemplarypharmaceutically acceptable carriers include sugars, starches,celluloses, powdered tragacanth, malt, gelatin; talc, and vegetableoils. Optional active agents may be included in a pharmaceuticalcomposition, which do not substantially interfere with the activity ofthe compound of the present invention.

The pharmaceutical compositions/combinations can be formulated for oraladministration. These compositions can contain any amount of activecompound that achieves the desired result, for example between 0.1 and99 weight % (wt. %) of the compound and usually at least about 5 wt. %of the compound. Some embodiments contain from about 25 wt. % to about50 wt. % or from about 5 wt. % to about 75 wt. % of the compound.

Formulations suitable for rectal administration are typically presentedas unit dose suppositories. These may be prepared by admixing the activecompound with one or more conventional solid carriers, for example,cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferablytake the form of an ointment, cream, lotion, paste, gel, spray, aerosol,or oil. Carriers which may be used include petroleum jelly, lanoline,polyethylene glycols, alcohols, transdermal enhancers, and combinationsof two or more thereof.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Formulationssuitable for transdermal administration may also be delivered byiontophoresis (see, for example, Pharmaceutical Research 3 (6):318(1986)) and typically take the form of an optionally buffered aqueoussolution of the active compound. In one embodiment, microneedle patchesor devices are provided for delivery of drugs across or into biologicaltissue, particularly the skin. The microneedle patches or devices permitdrug delivery at clinically relevant rates across or into skin or othertissue barriers, with minimal or no damage, pain, or irritation to thetissue.

Formulations suitable for administration to the lungs can be deliveredby a wide range of passive breath driven and active power drivensingle/-multiple dose dry powder inhalers (DPI). The devices mostcommonly used for respiratory delivery include nebulizers, metered-doseinhalers, and dry powder inhalers. Several types of nebulizers areavailable, including jet nebulizers, ultrasonic nebulizers, andvibrating mesh nebulizers. Selection of a suitable lung delivery devicedepends on parameters, such as nature of the drug and its formulation,the site of action, and pathophysiology of the lung.

The compounds described herein and the pharmaceutically acceptable saltscan be used as therapeutically active substances, e.g. in the form ofpharmaceutical preparations. The pharmaceutical preparations can beadministered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions.

The compounds described herein and the pharmaceutically acceptable saltsthereof can be processed with pharmaceutically inert, inorganic ororganic carriers for the production of pharmaceutical preparations.Lactose, corn starch or derivatives thereof, talc, stearic acids or itssalts and the like can be used, for example, as such carriers fortablets, coated tablets, dragées and hard gelatin capsules. Suitablecarriers for soft gelatin capsules are, for example, vegetable oils,waxes, fats, semi-solid and liquid polyols and the like. Depending onthe nature of the active substance no carriers are however usuallyrequired in the case of soft gelatin capsules. Suitable carriers for theproduction of solutions and syrups are, for example, water, polyols,glycerol, vegetable oil and the like. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain pharmaceuticallyacceptable auxiliary substances such as preservatives, solubilizers,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorants, salts for varying the osmotic pressure, buffers, maskingagents or antioxidants. They can also contain still othertherapeutically valuable substances.

Medicaments containing a compound of the present invention or apharmaceutically acceptable salt thereof and a therapeutically inertcarrier are also provided by the present invention, as is a process fortheir production, which comprises bringing one or more compounds ofFormula I and/or pharmaceutically acceptable salts thereof and, ifdesired, one or more other therapeutically valuable substances into agalenical administration form together with one or more therapeuticallyinert carriers.

The dosage can vary within wide limits and will, of course, have to beadjusted to the individual requirements in each particular case. In thecase of oral administration the dosage for adults can vary from about0.01 mg to about 1000 mg per day of a compound of general Formula VII,Formula XIII, or of the corresponding amount of a pharmaceuticallyacceptable salt thereof. The daily dosage may be administered as singledose or in divided doses and, in addition, the upper limit can also beexceeded when this is found to be indicated.

The following examples illustrate the present invention without limitingit, but serve merely as representative thereof. The pharmaceuticalpreparations conveniently contain about 1-500 mg, particularly 1-100 mg,of a compound of Formula XIV. Examples of compositions according to theinvention are:

Example A

Tablets of the following composition are manufactured in the usualmanner:

TABLE 1 possible tablet composition mg/tablet ingredient 5 25 100 500Compound of Formula VII or XIII 5 25 100 500 Lactose Anhydrous DTG 125105 30 150 Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450Magnesium Stearate 1 1 1 1 Total 167 167 167 831

Manufacturing Procedure

-   -   1. Mix ingredients 1, 2, 3 and 4 and granulate with purified        water.    -   2. Dry the granules at 50° C.    -   3. Pass the granules through suitable milling equipment.    -   4. Add ingredient 5 and mix for three minutes; compress on a        suitable press.

Example B-1

Capsules of the following composition are manufactured:

TABLE 2 possible capsule ingredient composition mg/capsule ingredient 525 100 500 Compound of Formula VII or XIII 5 25 100 500 Hydrous Lactose159 123 148 — Corn Starch 25 35 40 70 Talk 10 15 10 25 MagnesiumStearate 1 2 2 5 Total 200 200 300 600

Manufacturing Procedure

-   -   1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30        minutes.    -   2. Add ingredients 4 and 5 and mix for 3 minutes.    -   3. Fill into a suitable capsule.

The compound of Formula VII or XIII, lactose and corn starch are firstlymixed in a mixer and then in a comminuting machine. The mixture isreturned to the mixer; the talc is added thereto and mixed thoroughly.The mixture is filled by machine into suitable capsules, e.g. hardgelatin capsules.

Example B-2

Soft Gelatin Capsules of the following composition are manufactured:

TABLE 3 possible soft gelatin capsule ingredient composition ingredientmg/capsule Compound of Formula VII or XIII 5 Yellow wax 8 HydrogenatedSoya bean oil 8 Partially hydrogenated plant oils 34 Soya bean oil 110Total 165

TABLE 4 possible soft gelatin capsule composition ingredient mg/capsuleGelatin 75 Glycerol 85% 32 Karion 83 8 (dry matter) Titan dioxide 0.4Iron oxide yellow 1.1 Total 116.5

Manufacturing Procedure

The compound of Formula VII or XIII is dissolved in a warm melting ofthe other ingredients and the mixture is filled into soft gelatincapsules of appropriate size. The filled soft gelatin capsules aretreated according to the usual procedures.

Example C

Suppositories of the following composition are manufactured:

TABLE 5 possible suppository composition ingredient mg/supp. Compound ofFormula VII or XIII 15 Suppository mass 1285 Total 1300

Manufacturing Procedure

The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered compoundof Formula VII or XIII is added thereto and stirred until it hasdispersed completely. The mixture is poured into suppository molds ofsuitable size, left to cool; the suppositories are then removed from themolds and packed individually in wax paper or metal foil.

Example D

Injection solutions of the following composition are manufactured:

TABLE 6 possible injection solution composition ingredient mg/injectionsolution. Compound of Formula VII or XIII 3 Polyethylene Glycol 400 150acetic acid q.s. ad pH 5.0 water for injection solutions ad 1.0 ml

Manufacturing Procedure

The compound of Formula VII or XIII is dissolved in a mixture ofPolyethylene Glycol 400 and water for injection (part). The pH isadjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 m1 byaddition of the residual amount of water. The solution is filtered,filled into vials using an appropriate overage and sterilized.

Example E

Sachets of the following composition are manufactured:

TABLE 7 possible sachet composition ingredient mg/sachet Compound ofFormula VII or XIII 50 Lactose, fine powder 1015 Microcrystallinecellulose (AVICEL PH 102) 1400 Sodium carboxymethyl cellulose 14Polyvinylpyrrolidon K 30 10 Magnesium stearate 10 Flavoring additives 1Total 2500

Manufacturing Procedure

The compound of Formula VII or XIII is mixed with lactose,microcrystalline cellulose and sodium carboxymethyl cellulose andgranulated with a mixture of polyvinylpyrrolidone in water. Thegranulate is mixed with magnesium stearate and the flavoring additivesand filled into sachets.

VII. Use of Compounds

The compounds of Formula Ia, Formula Ib, Formula II, Formula III a,Formula IIIb, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-tof the present invention bind to the ubiquitously expressed E3 ligaseprotein cereblon (CRBN) and alter the substrate specificity of the CRBNE3 ubiquitin ligase complex, resulting in breakdown of intrinsicdownstream proteins. The present compounds are thus useful for thetreatment or prophylaxis of various cancers.

In one aspect, the present invention provides compounds Formula Ia,Formula Ib, Formula II, Formula III a, Formula IIIb, Formula IV, FormulaV, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, FormulaXI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XIV-a toXIV-x, or Formula XV-a to XV-t as described herein for use astherapeutically active substance.

In a further aspect, the present invention provides compounds of FormulaIa, Formula Ib, Formula II, Formula III a, Formula IIIb, Formula IV,Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X,Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, FormulaXIV-a to XIV-x, or Formula XV-a to XV-t as defined herein, for use inthe treatment or prophylaxis of cancer.

In a further aspect, the present invention provides the use of acompound of Formula Ia, Formula Ib, Formula II, Formula III a, FormulaIIIb, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, FormulaXIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-t asdefined herein for the treatment or prophylaxis of cancer.

In a further aspect, the present invention provides a method of treatingor preventing cancer, comprising administering a therapeuticallyeffective amount of a compound of Formula Ia, Formula Ib, Formula II,Formula III a, Formula IIIb, Formula IV, Formula V, Formula VI, FormulaVII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,Formula XIII, Formula XIV, Formula XV, Formula XIV-a to XIV-x, orFormula XV-a to XV-t as defined herein to a subject.

In a further aspect, the present invention provides the use of acompound of Formula Ia, Formula Ib, Formula II, Formula III a, FormulaIIIb, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, FormulaXIV, Formula XV Formula XIV-a to XIV-x, or Formula XV-a to XV-t asdefined herein for the manufacture of a medicament for the treatment orprophylaxis of cancer.

The compounds of Formula Ia, Formula Ib, Formula II, Formula III a,Formula IIIb, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,Formula XIV, Formula XV, Formula XIV-a to XIV-x, or Formula XV-a to XV-tmay also be used to prepare bifunctional degrader compounds by linkingthem to a protein-targeting moiety that binds to a target protein or toa target polypeptide, in analogy to the bifunctional compounds whichhave been described e.g. in WO2013020557, WO2013063560, WO 2013106643,WO2015160845, WO2016011906, WO2016105518, WO2017007612, WO2017024318,and WO2017117473.

GENERAL SYNTHETIC EXAMPLES

The preparation of compounds of the present invention may be carried outin sequential or convergent synthetic routes. Syntheses of the compoundsof the invention are shown in the following schemes 1-2 and in thedescription of the specific examples. The skills required for carryingout the reaction and purification of the resulting products are known tothose skilled in the art. The substituents and indices used in thefollowing description of the processes have the significance givenherein before unless indicated to the contrary.

In more detail, the compounds of the present invention can bemanufactured by the methods given below, by the methods given in theexamples or by analogous methods. Appropriate reaction conditions forthe individual reaction steps are known to a person skilled in the art.The reaction sequence is not limited to the one displayed in schemesbelow, however, depending on the starting materials and their respectivereactivity the sequence of reaction steps can be freely altered.Starting materials are either commercially available or can be preparedby methods analogous to the methods given below, by methods described inreferences cited in the description or in the examples, or by methodsknown in the art.

In more detail, the compounds of the present invention can bemanufactured by the methods given below, by the methods given in theexamples or by analogous methods. Appropriate reaction conditions forthe individual reaction steps are known to a person skilled in the art.The reaction sequence is not limited to the one displayed in schemes1-2, however, depending on the starting materials and their respectivereactivity the sequence of reaction steps can be freely altered.Starting materials are either commercially available or can be preparedby methods analogous to the methods given below, by methods described inreferences cited in the description or in the examples, or by methodsknown in the art.

The substituents are as described in the claims and Y is NH or CH₂

Step A: Amide bond formation can be accomplished by a coupling reactionbetween a spiro-piperidine 1 and a carboxylic acid 2 in the presence ofa coupling reagent such as DCC, EDC, TBTU or HATU in the presence of anorganic base such as triethylamine, N,N-diisopropylethylamine orN-methylmorpholine in halogenated solvents such as dichloromethane or1,2-dichloroethane or ethereal solvents such as diethyl ether, dioxane,THF, DME or TBME or polar non-protic organic solvent such asN,N-dimethylformamide at room temperature or at elevated temperaturesfor 2-18 hours.

Preferred conditions are HATU with N,N-diisopropylethylamine inN,N-dimethylformamide at room temperature for 15 hours.

Alternatively, amide bond formation can be accomplished by a couplingreaction between a spiro-piperidine 1 and an acyl chloride compound 2athat has been preformed in situ from a carboxylic acid 2. The acylchloride compound 2a can be prepared in situ from the correspondingcarboxylic acid 2 by treatment with1-chloro-N,N,2-trimethylpropenylamine (CAS 26189-59-3) in halogenatedsolvents such as dichloromethane or 1,2-dichloroethane, or in etherealsolvents such as diethyl ether, dioxane, THF, DME or TBME, at atemperature between 0° C. and room temperature, according to the methodof Ghosez and co-workers (J. Chem. Soc., Chem. Commun. 1979, 1180; Org.Synth. 1980, 59, 26-34). Amide bond formation can then be accomplishedby reaction of the acyl chloride compound 2a with spiro-piperidine 1 inthe presence of an organic base such as triethylamine,N,N-diisopropylethylamine or N-methylmorpholine in halogenated solventssuch as dichloromethane or 1,2-dichloroethane, or in ethereal solventssuch as diethyl ether, dioxane, THF, DME or TBME. Preferred conditionsare N,N-diisopropylethylamine in THE at room temperature for 1 hour.

The substituents are as described in the claims and Y is NH or CH₂. EWGis an electron-withdrawing group such as —CN, —CO₂R, —SO₂R or —NO₂ andhal is F or Cl

Step A: Nucleophilic aromatic substitution (S_(N)Ar) reaction can beaccomplished by reaction of a spiro-piperidine 1 with anelectron-deficient mono- or fused bicyclic heteroaromatic compound 4bearing a suitable leaving group such as fluorine or chlorine in thepresence of an organic base such as triethylamine,N,N-diisopropylethylamine or N-methylmorpholine in polar non-proticorganic solvent such as N,N-dimethylformamide or N-methylpyrrolidone atelevated temperature.

Examples of suitable spiro-piperidine compounds 1 include, but are notlimited to, 1,3,7-triazaspiro[4.4]nonane-2,4-dione (CAS 908099-69-4) or2,7-diazaspiro[4.4]nonane-1,3-dione (CAS 1308384-60-2), or theircorresponding salts 1,3,7-triazaspiro[4.4]nonane-2,4-dione hydrochloride(CAS 1334146-82-5) or 2,7-diazaspiro[4.4]nonane-1,3-dione hydrochloride(CAS 1609399-87-2).

Examples of suitable electron-deficient heteroaromatic compounds 4bearing a suitable leaving group include, but are not limited to,2-chlorobenzo[d]thiazole (CAS 615-20-3), methyl 6-chloronicotinate (CAS73781-91-6), or 2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4).Preferred conditions are N,N-diisopropylethylamine inN,N-dimethylformamide at 100° C. for 1 hour.

REPRESENTATIVE EXAMPLES OF THE PRESENT INVENTION

The following examples are provided for illustration of the invention.They should not be considered as limiting the scope of the invention,but merely as being representative thereof.

Isolation and purification of the compounds and intermediates describedherein can be effected, if desired, by any suitable separation orpurification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography,thick-layer chromatography, preparative low or high-pressure liquidchromatography or a combination of these procedures. Specificillustrations of suitable separation and isolation procedures can be hadby reference to the preparations and examples herein below. However,other equivalent separation or isolation procedures could, of course,also be used. Racemic mixtures of chiral compounds of the presentinvention can be separated using chiral HPLC. Racemic mixtures of chiralsynthetic intermediates may also be separated using chiral HPLC.

Example 1: Synthesis of7-Benzoyl-1,3,7-triazaspiro[4.4]nonane-2,4-dione: To a solution of1,3,7-triazaspiro[4.4]nonane-2,4-dione (100 mg, 645 μmol, eq: 1; CAS908099-69-4) and benzoic acid (82.6 mg, 677 μmol, eq: 1.05; CAS65-85-0), in N,N-dimethylformamide (1 m1) were added DIPEA (110 mg, 149μl, 851 μmol, eq: 4; CAS 7087-68-5) and HATU (121 mg, 319 μmol, eq: 1.5;CAS 148893-10-1). The reaction mixture was stirred at room temperaturefor 15 hours. The reaction mixture was partitioned between ethyl acetate(50 m1) and water (30 m1) and the layers were separated. The aqueouslayer was washed with two 20 m1 portions of ethyl acetate. The combinedorganic layers were washed with one 30 m1 portion of water/brine (1:1),dried over anhydrous sodium sulfate and concentrated in vacuo. The crudematerial was purified by preparative HPLC. (YMC-Triart C18, 12 nm, 5 μm,100×30 mm, CH₃CN/H₂O+0.1% HCOOH) to afford7-benzoyl-1,3,7-triazaspiro[4.4]nonane-2,4-dione (14.1 mg, 54.4 μmol,8.4% yield) as a white solid, MS (ISP): 260.0 ([M+H]⁺).

Example 2: Synthesis of7-((S)-1,2,3,4-Tetrahydronaphthalene-1-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione(EPIMERS 1:1): The title compound was obtained (as a 1:1 mixture ofepimers) in analogy to Example 1 using(S)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (CAS 85977-52-2) inplace of benzoic acid to afford a white solid. MS (ISP): 314.1 ([M+H]⁺).

Example 3: Synthesis of7-(Benzo[d]thiazol-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione: To asuspension of 2-chlorobenzo[d]thiazole (21.9 mg, 129 μmol, eq: 1; CAS615-20-3) and DIPEA (50 mg, 67.5 μl, 387 μmol, eq: 3) inN,N-dimethylformamide (435 μl) was added1,3,7-triazaspiro[4.4]nonane-2,4-dione (20 mg, 129 μmol, eq: 1; CAS908099-69-4). The reaction mixture was stirred at 100° C. for 1 hour.The reaction mixture was poured into ethyl acetate/tetrahydrofuran (1:1)and washed sequentially with water and with saturated brine. The organiclayer was dried over sodium sulfate and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 4 g, 0% to 5%methanol in dichloromethane) to afford7-(benzo[d]thiazol-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione (18 mg,62.4 μmol, 48.4% yield) as a white solid. MS (ISP): 289.2 ([M+H]⁺).

Example 4: Synthesis of7-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione:The title compound was obtained in analogy to Example 1 usingpyrazolo[1,5-a]pyridine-3-carboxylic acid (CAS 16205-46-2) in place ofbenzoic acid to afford a white solid. MS (ISP): 300.1 ([M+H]⁺).

Example 5: Synthesis of Methyl6-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinate: The titlecompound was obtained in analogy to Example 3 using methyl6-chloronicotinate (CAS 73781-91-6) in place of 2-chlorobenzo[d]thiazoleto afford a white solid. MS (ISP): 291.1 ([M+H]⁺).

Example 6: Synthesis ofN-(3-(2,4-Dioxo-1,3,7-triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide:The title compound was obtained in analogy to Example 1 using3-acetamidobenzoic acid (CAS 587-48-4) in place of benzoic acid toafford a white solid. MS (ISP): 633.3 ([2 M+H]⁺).

Example 7: Synthesis ofN-(4-(2,4-Dioxo-1,3,7-triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide:The title compound was obtained in analogy to Example 1 using4-acetamidobenzoic acid (CAS 556-08-1) in place of benzoic acid toafford a white solid. MS (ISP): 317.1 ([M+H]⁺).

Example 8: Synthesis of7-(Thiazolo[4,5-b]pyridin-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione:The title compound was obtained in analogy to Example 3 using2-chlorothiazolo[4,5-b]pyridine (CAS 152170-30-4) in place of2-chlorobenzo[d]thiazole to afford a white solid. MS (ISP): 290.0([M+H]⁺).

Example 9: Synthesis of7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione:The title compound was obtained in analogy to Example 1 usingbenzo[d]thiazole-5-carboxylic acid (CAS 68867-17-4) in place of benzoicacid to afford a white solid. MS (ISP): 317.0 ([M+H]⁺).

Example 10: Synthesis of Methyl6-(6,8-dioxo-2,7-diazaspiro[4.4]nonan-2-yl)nicotinate

Step a) Synthesis of 7-Benzyl-2,7-diazaspiro[4.4]nonane-1,3-dione:1-Benzyl-3-(carboxymethyl)pyrrolidine-3-carboxylic acid (310 mg, 1.18mmol, eq: 1; CAS 885958-89-4) and urea (141 mg, 2.35 mmol, eq: 2; CAS57-13-6) were combined. The neat reaction mixture was heated at 200° C.for 1 hour. The reaction mixture was poured into tetrahydrofuran andwashed with brine. The organic layer was dried over sodium sulfate andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 12 g, 0% to 10% methanol in dichloromethane)to afford 7-benzyl-2,7-diazaspiro[4.4]nonane-1,3-dione (133 mg, 544μmol, 46.2% yield) as a colorless amorphous oil. MS (ISP): 245.2([M+H]⁺).

Step b) Synthesis of 2, 7-Diazaspiro[4.4]nonane-1,3-dione hydrochloride:To a solution of 7-benzyl-2,7-diazaspiro[4.4]nonane-1,3-dione (130 mg,532 μmol, eq: 1) in methanol (40 m1) was added 10% palladium on charcoal(28.3 mg, 26.6 μmol, eq: 0.05). The reaction mixture was stirred at roomtemperature for 3 hours under an atmosphere of hydrogen. The catalystwas collected by filtration washing with methanol. To the filtrate wasadded a 2 M solution of HCl in Et₂O (5.32 m1, 10.6 mmol, eq: 20). Thefiltrate was then concentrated in vacuo. The product was dissolved inwater and freeze-dried to afford 2,7-diazaspiro[4.4]nonane-1,3-dionehydrochloride (91 mg, 477 μmol, 89.7% yield) as a white solid. MS (ISP):155.1 ([M+H]⁺).

Step c) Synthesis of Methyl6-(6,8-dioxo-2,7-diazaspiro[4.4]nonan-2-yl)nicotinate: To a suspensionof 2,7-diazaspiro[4.4]nonane-1,3-dione hydrochloride (25 mg, 131 μmol,eq: 1) and methyl 6-chloronicotinate (22.5 mg, 131 μmol, eq: 1; CAS73781-91-6) in N,N-dimethylformamide (0.5 m1) was added DIPEA (50.9 mg,68.7 μl, 393 μmol, eq: 3). The reaction mixture was stirred at 100° C.for 2 hours. The reaction mixture was poured into ethylacetate/tetrahydrofuran (1:2) and washed with brine. The organic layerwas dried over sodium sulfate and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 4 g, 0% to10% methanol in dichloromethane) to afford methyl6-(6,8-dioxo-2,7-diazaspiro[4.4]nonan-2-yl)nicotinate (13 mg, 44.9 μmol,34.3% yield) as a white solid. MS (ISP): 290.0 ([M+H]⁺).

Example 11: Synthesis of7-(Benzo[d]thiazol-2-yl)-2,7-diazaspiro[4.4]nonane-1,3-dione: The titlecompound was obtained in analogy to Example 10, Step c using2-chlorobenzo[d]thiazole (CAS 615-20-3) in place of methyl6-chloronicotinate to afford a white solid. MS (ISP): 288.0 ([M+H]⁺).

Example 12: Synthesis of7-(Pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.4]nonane-1,3-dione:To a suspension of pyrazolo[1,5-a]pyridine-3-carboxylic acid (18 mg, 111μmol, eq: 1; CAS 16205-46-2) in tetrahydrofuran (0.5 m1) was added1-chloro-N,N,2-trimethylpropenylamine (17.8 mg, 17.6 μl, 133 μmol, eq:1.2; CAS 26189-59-3) at 0-5° C. The reaction mixture was stirred at roomtemperature for 1 hour to give a yellow solution. The acid chloridesolution was then added to a suspension of2,7-diazaspiro[4.4]nonane-1,3-dione hydrochloride (21.2 mg, 111 μmol,eq: 1) and DIPEA (43 mg, 58.2 μl, 333 μmol, eq: 3) in tetrahydrofuran(0.5 m1). The reaction mixture was stirred at room temperature for 30minutes. The reaction mixture was poured into ethylacetate/tetrahydrofuran (1:3) and washed with brine. The organic layerwas dried over sodium sulfate and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 4 g, 0% to10% methanol in dichloromethane) to afford7-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2,7-diazaspiro[4.4]nonane-1,3-dione(9 mg, 30.2 μmol, 27.2% yield) as a white solid MS (ISP): 299.1([M+H]⁺).

Example 13: Synthesis of 7-Benzoyl-2,7-diazaspiro[4.4]nonane-1,3-dione:To a suspension of 2,7-diazaspiro[4.4]nonane-1,3-dione hydrochloride (21mg, 110 μmol, eq: 1) and DIPEA (42.7 mg, 57.7 μl, 330 μmol, eq: 3) intetrahydrofuran (0.5 m1) was added benzoyl chloride (15.5 mg, 12.8 μl,110 μmol, eq: 1; CAS 98-88-4) in tetrahydrofuran (0.5 m1). The reactionmixture was stirred at room temperature for 1 hour. The reaction mixturewas poured into ethyl acetate/tetrahydrofuran (1:3) and washed withbrine. The organic layer was dried over Na₂SO₄ and concentrated invacuo. The crude material was purified by flash chromatography (silicagel, 4 g, 0% to 10% methanol in dichloromethane) to afford7-benzoyl-2,7-diazaspiro[4.4]nonane-1,3-dione (7 mg, 27.1 μmol, 24.6%yield) as a white solid. MS (ISP): 259.0 ([M+H]⁺).

Example 14: Synthesis of7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione(ENANTIOMER 1): The enantiomers of7-(benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione(Example 9) were separated using chiral HPLC: Reprosil Chiral NR columnwith n-heptane/ethanol+NH₄OAc: (60:40) affording7-(benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione(ENANTIOMER 1) (4.7 mg, white solid), retention time=11.7 min. MS (ISP):317.0 ([M+H]⁺).

Example 15: Synthesis of7-(Benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione(ENANTIOMER 2): The enantiomers of7-(benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione(Example 9) were separated using chiral HPLC: Reprosil Chiral NR columnwith n-heptane/ethanol+NH₄₀Ac: (60:40) affording7-(benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione(ENANTIOMER 2) (5.1 mg, white solid), retention time=12.3 min. MS (ISP):317.0 ([M+H]⁺).

Pharmacological Tests

The compounds of the present invention and their pharmaceuticallyacceptable salts possess valuable pharmacological properties. Thecompounds were investigated in accordance with the test givenhereinafter.

Dual Fluorescent Reporter Assay

In order to measure BRD4 protein abundance in a mammalian cell system atmedium throughput, a dual fluorescent reporter system was developedbased on a principle described in Collins et al., Biochem J, 2017,474(7), 1127-1147. Transient expression vectors were designed thatcontain the BRD4 coding sequence (NM_058243.2) fused to a fluorescenttag. Vectors were synthesized at ATUM (Newark, CA, USA) using the pD2610CMV backbone and were built up as follows: c-terminal versionBRD4_eGFP—IRES—FresnoRFP_NLS, n-terminal versioneGFP_BRD4—IRES—FresnoRFP_NLS, empty vector controleGFP—IRES—FresnoRFP_NLS. The c-terminal version was used for thereporter assays, as it presented with the best assay window. HEK293Acells (Invitrogen, Cat. No. R705-07) were cultured in Dulbecco'sModified Eagle Medium (DMEM), 10% fetal calf serum, 2 mM L-Glutamine, 1%Penicillin/Streptomycin. Transfections of the plasmids were performedwith Lipofectamine 2000 according to the manufacturer's protocol(Invitrogen, Carlsbad, CA, USA). 40 hours after transfection, cells wereseeded at a density of 40'000/100 μl/96 well flat-bottom and 8 hourslater treated with compounds (stocks 10 mM in DMSO) at a 10-pointdilution ranging from 0-25 μM. After 16 hours of treatment, cells werewashed with PBS, resuspended in Accumax solution (Sigma-Aldrich Cat. No.A7089) and analyzed by flow-cytometry (CytoFlex S, BeckmanCoulter).Single cells were gated based on their forward and side-scatter profilesand pulse-width was used to exclude doublets. A minimum of 20'000 cellswas acquired per sample. Analysis was performed with the program Flow JoV10.1 on BRD4-eGFP low/medium cells (<106 FL1-A Mean FluorescenceIntensity (MFI)). A factor was derived to normalize BRD4-eGFP values tothe RFP protein abundance control (20×FL1A-GFP/FL11A-RFP), then Medianand Mode values were calculated and used for comparisons betweentreatment conditions.

Capillary-Based Immunoassays to Measure Endogenous BRD4 Levels

The biological activity of selected compounds (cut-off >20% reduction inBRD4-eGFP levels) was confirmed in an additional assay which allowed thequantification of endogenous BRD4 levels. To this end, HEK293A cells(origin and culture conditions see above) were seeded at 400'000/300μl/48 well and were treated 6 hours later with compound concentrationsas indicated for. 16 hours after the treatment, the cells were washedwith PBS and lysed in 50 μl of UREA lysis buffer (10 mM Tris-HCl pH 8,2% CHAPS, 7M UREA, 0.4% DTT), supplemented with 1×protease inhibitorcocktail (Complete Mini, Roche) and 1×phosphatase inhibitor cocktail(PhosSTOP, Sigma-Aldrich). Samples were then analyzed by Peggy Sue orWES capillary-based immunoassay systems according to the manufacturer'sprotocol (Protein Simple/Bio-Techne, San Jose, California, 95134 USA).Antibodies used were anti-BRD4 (Cell signaling, CST 13440 1:50) andanti-Vinculin (Sigma, V9131, 1:4000). To quantify BRD4 protein levels,the peak signal areas were normalized to the vinculin loading controland to the DMSO condition (Yen, H.-C. S., et al. Global ProteinStability Profiling in Mammalian Cells. Science 322, 918-923,doi:10.1126/science.1160489 (2008)).

Fluorescence Direct Binding Protocol

Determination of the affinities of compounds to protein containing oneor more tryptophan is measurable by monitoring the fluorescence emissionin direct mode. The measurements depending on the protein availableamounts are performed either manually in a cuvette on ISS-PC1 photoncounting spectrofluorometer or automatically in well plates on afluorescence plate reader device. Fluorescence titrations are performedat 20° C. in the chosen binding assay buffer by using a defined constantprotein concentration against ligand concentration variations. Smallaliquots of known ligand concentration solubilized in DMSO were addedand the fluorescence, excited at 280 nm, was recorded at 340 nm. Thefluorescence intensity was corrected for protein dilution and for thefilter effect (Birdsall, B., et al. (1983). Anal. Biochem. 132,353-361). The corrected fluorescence intensity was plotted against theligand concentration and fitted using a four-parameter sigmoidalfunction, from which the equilibrium dissociation constant K_(d) wascomputed using the law of mass action assuming a 1:1 protein-ligandcomplex (Eftink, Methods Enzymol. 1997; 278:221-57).

The Fluorescence Direct Binding Protocol Process includes:

-   -   1) Optimization of measurement parameters to minimize protein        consumption and to minimize the dilution effect and the DMSO        content    -   2) Titration measurements of the protein against ligand by at        least 12 titration steps to obtain a good s-curve fit    -   3) Repeat the same titration measurements with the ligand alone        to enable correction    -   4) Check the stability of the protein once by titration against        DMSO alone    -   5) Determination of the molar extinction coefficients of the        ligand at 280 and 340 nm with help of an UV-spectrophotometer    -   6) Use Excel template for the correction of the measured raw        data    -   7) Use GraphPad Prism software for the quadratic binding fit and        the K_(D) evaluation.

TABLE 8 Description of Protein and buffers (Reference compound:Thalidomide) Protein Batch # Cereblon_17_13 Construct namehCereblon(M1-L442)_hDDB1(M1-H1140) Concentration 2.54 mg/ml MW 180180 DaMolar extinction □₂₈₀ = 165045 M⁻¹ · cm⁻¹ coefficient Storage buffer 20mM MES pH 6.5 200 mM NaCl 1 mM TCEP Assay buffer 50 mM Hepes 7.4 200 mMNaCl

TABLE 9 Settings of ISS-PCI Device ISS-PC1 Excitation wavelength [nm]280 Emission wavelength [nm] 340 Cuvette Hellma 115F-QS Volume [μL] 500

TABLE 10 Protein Preparation Volume Protein [μL] Volume buffer [μL]Protein concentration [M] 1.8 @ 2.54 mg/ml 498.2 5.0 E−8

TABLE 11 Titration Steps C Aliquot V Aliquot Dilution C Lig [M] [M] [μL]C Prot[M] factor    1E−10 1.0E−07 0.5 4.995E−08 1.001  1.1E−09 1.0E−060.5 4.990E−08 1.002  3.1E−09 1.0E−06 1 4.980E−08 1.004  5.1E−09 1.0E−061 4.970E−08 1.006  1.51E−08 1.0E−05 0.5 4.965E−08 1.007  2.51E−081.0E−05 0.5 4.960E−08 1.008  4.51E−08 1.0E−05 1 4.950E−08 1.01  6.51E−08 1.0E−05 1 4.941E−08 1.012 1.651E−07 1.0E−04 0.5 4.936E−081.013 3.651E−07 1.0E−04 1 4.926E−08 1.015 5.651E−07 1.0E−04 1 4.916E−081.017 7.651E−07 1.0E−04 1 4.907E−08 1.019 9.651E−07 1.0E−04 1 4.897E−081.021 1.9651E−06  1.0E−03 0.5 4.892E−08 1.022 2.9651E−06  1.0E−03 0.54.888E−08 1.023 1.29651E−05  1.0E−02 0.5 4.883E−08 1.024 2.29651E−05 1.0E−02 0.5 4.878E−08 1.025 4.29651E−05  1.0E−02 1 4.869E−08 1.0276.29651E−05  1.0E−02 1 4.859E−08 1.029 8.29651E−05  1.0E−02 1 4.850E−081.031

TABLE 12 Affinities of Select Compounds to Protein Fluorescenceh-Cereblon_DDB1 Mean Ex. Name Structure K_(d)_EQ (μM) 1 7-benzoyl-1,3,7-triazaspiro[4.4]nonane-2,4-dione

0.00400 2 7-((S)-1,2,3,4- tetrahydronaphthalene-1-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4- dione

0.00300 3 7-(benzo[d]thiazol-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione

0.03100 4 7-(pyrazolo[1,5-a]pyridine-3- carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione

0.03700 5 methyl 6-(2,4-dioxo-1,3,7- triazaspiro[4.4]nonan-7-yl)nicotinate

0.00200 6 N-(3-(2,4-dioxo-1,3,7- triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide

0.01 7 N-(4-(2,4-dioxo-1,3,7- triazaspiro[4.4]nonane-7-carbonyl)phenyl)acetamide

0.161 8 7-(thiazolo[4,5-b]pyridin-2-yl)-1,3,7-triazaspiro[4.4]nonane-2,4- dione

0.007 9 7-(benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4- dione

0.03200 10 methyl 6-(6,8-dioxo-2,7- diazaspiro[4.4]nonan-2-yl)nicotinate

0.01000 11 7-(benzo[d]thiazol-2-yl)-2,7- diazaspiro[4.4]nonane-1,3-dione

0.01800 12 7-(pyrazolo[1,5-a]pyridine-3- carbonyl)-2,7-diazaspiro[4.4]nonane-1,3-dione

0.00600 13 7-benzoyl-2,7- diazaspiro[4.4]nonane-1,3-dione

0.01500 14 (R)-7-(benzo[d]thiazole-5- carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione

0.02600 15 (S)-7-(benzo[d]thiazole-5-carbonyl)-1,3,7-triazaspiro[4.4]nonane-2,4- dione

0.02300

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for the purposes of clarity ofunderstanding, it will be readily apparent to one of ordinary skill inthe art in light of the teaching of this invention that certain changesand modification may be made thereto without departing from the spiritor scope of the invention as defined in the claims.

We claim:
 1. A compound of formula,

or a pharmaceutically acceptable salt thereof, wherein: Y is NH or CH₂;n is 0 or 1; A is selected from the group consisting of i.) aryl; ii.)aryl substituted by R¹; iii.) heteroaryl; and iv.) heteroarylsubstituted by R²; R¹ is selected from the group consisting of i.)—C(═O)—O—C₁₋₆-alkyl; ii.) —COOH; iii.) —NH—C(═O)—C₁₋₆-alkyl; iv.) —NH₂;and v.) —NO₂; R² is selected from the group consisting of i.) —COOH;ii.) —C(═O)—O—C₁₋₆-alkyl; iii.) —NH₂; and iv.) —NO₂.
 2. The compound ofclaim 1, wherein A is aryl.
 3. The compound of claim 1, wherein A isheteroaryl.
 4. The compound of claim 2, wherein Y is NH and n is
 0. 5.The compound of claim 2, wherein Y is NH and n is
 1. 6. The compound ofclaim 2, wherein Y is CH₂ and n is
 0. 7. The compound of claim 2,wherein Y is CH₂ and n is
 1. 8. The compound of claim 3, wherein Y is NHand n is
 0. 9. The compound of claim 3, wherein Y is NH and n is
 1. 10.The compound of claim 3, wherein Y is CH₂ and n is
 0. 11. The compoundof claim 3, wherein Y is CH₂ and n is
 1. 12. A pharmaceuticalcomposition comprising a compound of claim 1, and a therapeuticallyinert carrier.
 13. A method of treating cancer in a subject in needthereof comprising administering an effective amount of a compound ofclaim 1, or a pharmaceutically acceptable salt thereof, optionally in apharmaceutical composition.
 14. The method of claim 13, wherein thesubject is a human.